# Patent

## Title
Peptide/particle delivery systems

## Abstract

Polymeric nanoparticles, microparticles, and gels for delivering cargo, e.g., a therapeutic agent, such as a peptide, to a target, e.g., a cell, and their use for treating diseases, including angiogenesis-dependent diseases, such as age-related macular degeneration and cancer, are disclosed. Methods for formulating, stabilizing, and administering single peptides or combinations of peptides via polymeric particle and gel delivery systems also are disclosed.

## Background
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of U.S. Provisional Application Nos. 61/392,224, filed Oct. 12, 2010; 61/542,995, filed Oct. 4, 2011; and 61/543,046, filed Oct. 4, 2011, each which is incorporated herein by reference in its entirety.
This application is also a continuation-in-part of and claims priority to PCT Application No. PCT/US2010/035127 filed May 17, 2010, which claims benefit of U.S. provisional application no. 61/178,611, filed May 15, 2009.


FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
This invention was made in part with the United States Government support under CA131931 and CA152473 awarded by the National Institutes of Health (NIH). The U.S. Government has certain rights in the invention.


SEQUENCE LISTING
The instant application contains a Sequence Listing which has been submitted in ASCII format via EFS-Web and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Dec. 28, 2011, is named P1125002.txt and is 379,467 bytes in size.
BACKGROUND
Biomaterials have the potential to significantly impact medicine as delivery systems for imaging agents, biosensors, drugs, and genes. Farokhzad O C. Nanotechnology for drug delivery: the perfect partnership. Expert Opin Drug Deliv 2008; 5(9):927-9; Putnam D. Polymers for gene delivery across length scales. Nat Mater 2006; 5(6):439-51; Brigger I, Dubernet C, Couvreur P. Nanoparticles in cancer therapy and diagnosis. Adv Drug Deliv Rev 2002;54(5):631-51. Challenges exist, however, in creating a delivery vehicle capable of effective, safe, and controlled release of sensitive biomolecules. Although rapid advances have been made for sustained delivery of small molecule drugs using biotechnology, similar advances have not been made for the delivery of peptides, siRNA, or combinations of biological agents.
SUMMARY
The presently disclosed subject matter provides polymeric nanoparticles, microparticles, and gels for delivering cargo, e.g., a therapeutic agent, such as a peptide, to a target, e.g., a cell, and their use for treating multiple diseases, including angiogenesis-dependent diseases, such as age-related macular degeneration and cancer. Methods for formulating, stabilizing, and administering single peptides or combinations of peptides via polymeric particle and gel delivery systems, for example, using a controlled release strategy, also are disclosed.
In some aspects, the presently disclosed subject matter provides a bioreducible, hydrolytically degradable polymer of formula (Ia):




wherein:

n is an integer from 1 to 10,000;
R1, R2, R3, R4, R5, R6, R7, R8, and R9 are each independently selected from the group consisting of hydrogen, branched and unbranched alkyl, branched and unbranched alkenyl, branched and unbranched alkynyl, aryl, halogen, hydroxyl, alkoxy, carbamoyl, carboxyl ester, carbonyldioxyl, amide, thiohydroxyl, alkylthioether, amino, alkylamino, dialkylamino, trialkylamino, cyano, ureido, a substituted alkanoyl group, cyclic, cyclic aromatic, heterocyclic, and aromatic heterocyclic groups, each of which may be substituted with at least one substituent selected from the group consisting of branched or unbranched alkyl, branched and unbranched alkenyl, branched and unbranched alkynyl, amino, alkylamino, dialkylamino, trialkylamino, aryl, ureido, heterocyclic, aromatic heterocyclic, cyclic, aromatic cyclic, halogen, hydroxyl, alkoxy, cyano, amide, carbamoyl, carboxylic acid, ester, carbonyl, carbonyldioxyl, alkylthioether, and thiohydroxyl groups;
wherein R1 can be present or absent and when present the compound of formula (I) further comprises a counter ion selected from the group consisting of chloride, fluoride, bromide, iodide, sulfate, nitrate, fumarate, acetate, carbonate, stearate, laurate, and oleate; and
wherein at least one R comprises a backbone of a diacrylate having the following structure:




wherein X1 and X2 are each independently substituted or unsubstituted C2-C20 alkylene, and wherein each X1 and X2 can be the same or different.
In other aspects, the presently disclosed subject matter provides a nanoparticle, microparticle, or gel comprising a compound of formula (I):




wherein:

n is an integer from 1 to 10,000;
R1, R2, R3, R4, R5, R6, R7, R8, and R9 are each independently selected from the group consisting of hydrogen, branched and unbranched alkyl, branched and unbranched alkenyl, branched and unbranched alkynyl, aryl, halogen, hydroxyl, alkoxy, carbamoyl, carboxyl ester, carbonyldioxyl, amide, thiohydroxyl, alkylthioether, amino, alkylamino, dialkylamino, trialkylamino, cyano, ureido, a substituted alkanoyl group, cyclic, cyclic aromatic, heterocyclic, and aromatic heterocyclic groups, each of which may be substituted with at least one substituent selected from the group consisting of branched or unbranched alkyl, branched and unbranched alkenyl, branched and unbranched alkynyl, amino, alkylamino, dialkylamino, trialkylamino, aryl, ureido, heterocyclic, aromatic heterocyclic, cyclic, aromatic cyclic, halogen, hydroxyl, alkoxy, cyano, amide, carbamoyl, carboxylic acid, ester, carbonyl, carbonyldioxyl, alkylthioether, and thiohydroxyl groups;
wherein R1 can be present or absent and when present the compound of formula (I) further comprises a counter ion selected from the group consisting of chloride, fluoride, bromide, iodide, sulfate, nitrate, fumarate, acetate, carbonate, stearate, laurate, and oleate; and
at least one of R, R′, and R′′comprise a reducible or degradable linkage, and wherein each R, R′, or R′′ can independently be the same or different;
under the proviso that when at least one R group comprises an ester linkage of the formula —C(═O)—O— and the compound of formula (I) comprises a poly(beta-amino ester), then the compound of formula (I) must also comprise one or more of the following characteristics:
(a) each R group is different;
(b) each R′′ group is different;
(c) each R′′ group is not the same as any of R′, R1, R2, R3, R4, R5, R6, R7, R8, and R9;
(d) the R′′ groups degrade through a different mechanism than the ester-containing R groups, wherein the degradation of the R′′ group is selected from the group consisting of a bioreducible mechanism or an enzymatically degradable mechanism; and/or
(e) the compound of formula (I) comprises a substructure of a larger cross-linked polymer, wherein the larger cross-linked polymer comprises different properties from compound of formula (I);
and one or more peptides selected from the group consisting of an anti-angiogenic peptide, an anti-lymphangiogenic peptide, an anti-tumorigenic peptide, and an anti-permeability peptide.
In other aspects, the presently disclosed subject matter provides a multilayer particle comprising a core and one or more layers, wherein the core comprises a material selected from the group consisting of a compound of formula (I), a gold nanoparticle, an inorganic nanoparticle, an organic polymer, and the one or more layers comprise a material selected from the group consisting of a compound of formula (I), an organic polymer, one or more peptides, and one or more additional biological agents. In yet other aspects, the presently disclosed subject matter provides a microparticle comprising a compound of formula (I), poly(lactide-co-glycolide) (PLGA), or combinations thereof.
In other aspects, the presently disclosed subject matter provides a method for stabilizing a suspension of nanoparticles and/or microparticles of formula (I), the method comprising: (a) providing a suspension of nanoparticles and/or microparticles of formula (I); (b) admixing a lyroprotectant with the suspension; (c) freezing the suspension for a period of time; and (d) lyophilizing the suspension for a period of time.
In further aspects, the presently disclosed subject matter provides a pellet or scaffold comprising one or more lyophilized particle, wherein the one or more lyophilized particle comprises a compound of formula (I).
In yet further aspects, the presently disclosed subject matter provides a method of treating a disease or condition, the method comprising administering to a subject in need of treatment thereof a therapeutically effective amount of a nanoparticle, microparticle, gel, or multilayer particle comprising a compound of formula (I), wherein the nanoparticle, microparticle, gel, or multilayer particle further comprises a therapeutic agent specific for the disease or condition to be treated. In some aspects, the disease or condition comprises an angiogenesis-dependent disease or condition, including, but not limited to, cancer and age-related macular degeneration. In other aspects, the disease or condition is a non-angiogenic disease or condition. In certain aspects, the therapeutic agent encapsulated with the presently disclosed particles can be selected from the group consisting of gene, DNA, RNA, siRNA, miRNA, is RNA, agRNA, smRNA, a nucleic acid, a peptide, a protein, a chemotherapeutic agent, a hydrophobic drug, a small molecule drug, and combinations thereof.
Certain aspects of the presently disclosed subject matter having been stated hereinabove, which are addressed in whole or in part by the presently disclosed subject matter, other aspects will become evident as the description proceeds when taken in connection with the accompanying Examples and Figures as best described herein below.



BRIEF DESCRIPTION OF THE FIGURES
Having thus described the presently disclosed subject matter in general terms, reference will now be made to the accompanying Figures, which are not necessarily drawn to scale, and wherein:
FIG. 1 is an illustration of the presently disclosed multilayer particles;
FIG. 2 is a scheme for producing hydrogels comprising the presently disclosed materials.
FIG. 3 shows a scheme for producing stable nanoparticle suspensions;
FIGS. 4A-4D show representative polymer structures tuned to peptide cargos (FIG. 4A discloses SEQ ID NOS 2485 and 2484, respectively, in order of appearance. FIG. 4B discloses SEQ ID NO: 2388. FIG. 4C discloses SEQ ID NO: 2483. FIG. 4D discloses SEQ ID NO: 2452.);
FIGS. 5A and 5B show representative formation and sizing of polymer/peptide nanoparticles (by nanoparticle tracking analysis on a Nanosight LM10) (FIG. 5A discloses “DEAH” as SEQ ID NO: 2484);
FIG. 6 shows DEAH peptide (SEQ ID NO: 2484) release by 336 nanoparticles at 4° C (above) and 37° C (below);
FIG. 7 shows HUVEC viability/proliferation assays with polymer/SP6001 /DEAH peptide (“DEAH” disclosed as SEQ ID NO: 2484);
FIG. 8 shows HUVEC migration assays with 336 polymer/DEAH peptide (“DEAH” disclosed as SEQ ID NO: 2484);
FIG. 9 shows in vivo 336 polymer nanoparticle/SP6001 DEAH peptide (“DEAH” disclosed as SEQ ID NO: 2484);
FIG. 10 shows (top) Particle size and (bottom) cell viability effects of various polymer/SP2012 nanoparticles as compared to peptide only of non-cytotoxic polymers;
FIG. 11 shows polymer/peptide formulations for alternative peptides;
FIG. 12 shows data for FITC-tagged bovine serum albumin (BSA) mixed with a macromer solution containing 10% (w/v) PEGDA (Mn ̃270 Da) with various amounts of B4S4, dissolved in a 1:1 (v/v) mixture of DMSO and PBS;
FIG. 13 shows an SEM of increasing B4S4 from top [0.2% w/w] to bottom [5% w/w]);
FIG. 14 shows the size distribution of appropriately freeze-dried particles (bottom left, right-most histogram) remains the same as freshly-prepared particles (bottom left, left-most histogram). Freeze-dried particles also remain more stable in serum-containing medium than freshly-prepared particles (upper left). Using DNA-loaded nanoparticles, transfection efficiency is comparable between fresh particles and particles lyophilized with sucrose (right) even after 3 months of storage;
FIG. 15 is Left: brightfield+GFP+DsRed, showing presence of cells (green) being transfected with DsRed (red) on a bone scaffold (brightfield). Right: GFP and DsRed shown only;
FIG. 16 demonstrates that DsRed expression was observed within 4 days and remained very robust even after 12 days: top=1 day, middle=4 days, bottom=12 days after transfection;
FIG. 17 demonstrates the incorporation of DNA-loaded nanoparticles into natural and synthetic scaffolds, disks, microparticles, and hydrogels;
FIG. 18 demonstrates transfection of GFP+ glioblastoma cells with scrambled (control) siRNA (top panels) or siRNA against GFP (bottom);
FIGS. 19A-19C show activity of R6-series polymers at delivering siRNA to knockdown GFP signal in GB cells; % Knockdown of GFP expression in GFP+ glioblastoma cells transfected with siRNA against GFP, normalized to cells transfected with scrambled siRNA, using various BR6 polymers as a transfection agent: (A) transfection with acrylate-terminated BR6 polymers with either S3, S4 or S5 as the side chain; (B) transfection with E10 end-capped versions of the polymers in Figure A; and (C) GFP fluorescence images of cells transfected with BR6-S4-Ac complexed scrambled RNA (top) vs. siRNA against GFP (bottom);
FIG. 20 shows gel retardation assay of siRNA with BR6-S5-E10 at varying ratios of polymer to RNA. The polymer effectively retards siRNA (top), but in the presence of 5 mM glutathione siRNA is released immediately (bottom). These data demonstrate the hypothesized intracellular release of siRNA and elucidates the mechanism by which nanoparticles formed using BR6 facilitate strong siRNA transfection and GFP knockdown;
FIG. 21 shows that an E10-endcapped polymer (top) retards siRNA efficiently, but upon addition of 5 mM glutathione, siRNA is immediately released (bottom). Numbers refer to the w/w ratio of polymer-to-siRNA in all cases;
FIG. 22 shows that the same base polymer as shown in FIG. 25 with a different endcap (E7, 1-(3-aminopropyl)-4-methylpiperazine) also retards siRNA (top) but is not affected by application of glutathione (bottom);
FIG. 23 provides gel permeation chromatography data of BR6 polymerized with S4 at a BR6:S4 ratio of 1.2:1 at 90° C. for 24 hours, before and after end-capping with E7;
FIG. 24 shows that knockdown efficiency also is affected by molecular weight of the polymer. 1.2:1, 1.1:1, and 1.05:1 refer to the ratio of reactants in the base polymer step growth reaction;
FIG. 25 demonstrates combined DNA (RFP) and siRNA delivery (against GFP) in GB;
FIG. 26 shows that siRNA knockdown is affected by the endcap (E), base polymer (increasing hydrophobicity from L to R within each E), and molecular weight (increasing L to R within each base polymer);
FIG. 27 shows 4410, 200 w/w (blue line on above graph), 8 days after transfection: Left: hMSCs treated with scrambled control; Right: hMSCs treated with siRNA;
FIG. 28 demonstrates that in variable molecular weight embodiments, polymer molecular weight is between 4.00-10.00 kDa for siRNA delivery;
FIG. 29 demonstrates the use of the presently disclosed materials for DNA delivery;
FIG. 30 shows GB Transfection;
FIG. 31 shows 551 GB cells cultured as neurospheres (undifferentiated);
FIG. 32 demonstrates that, for a DNA delivery application, in some embodiments, polymer molecular weight is between 3.00-10.0 kDa;
FIG. 33 provides representative characteristics exhibited by the presently disclosed biodegradable polymers;
FIG. 34 demonstrates the delivery of DNA to GB bulk tumor cells for representative biomaterials;
FIG. 35 demonstrates the transfection of genes to BCSC for representative presently disclosed biomaterials;
FIG. 36 demonstrates the delivery of DNA to fetal (healthy) cells;
FIG. 37 demonstrates the delivery of DNA to BCSCs;
FIGS. 38 and 39 demonstrate the delivery of apoptosis-inducing genes in BCSCs;
FIG. 40 shows that particles lyophilized with sucrose and used immediately are as effective in transfection as freshly prepared particles;
FIGS. 41 and 42 demonstrate the use of the presently disclosed materials and methods for long-term gene delivery;
FIG. 43 demonstrates siRNA delivery to GB cells;
FIGS. 44 and 45 provide a comparison of siRNA vs. DNA delivery in GB cells;
FIG. 46 depicts a strategy of combining nanoparticles within microparticles to extend release further. PLGA or blends of PLGA with the presently disclosed polymers are used to form microparticles by single or double emulsion;
FIG. 47 shows DEAH-FITC release from microparticles comprising a presently disclosed polymer and a peptide (“DEAH” disclosed as SEQ ID NO: 2484);
FIG. 48 shows slow extended release from microparticles containing nanoparticles that contain peptides; and
FIG. 49 shows in vivo effects of microparticle formulations in both the CNV and rho/VEGF model over time.



DETAILED DESCRIPTION
The presently disclosed subject matter now will be described more fully hereinafter with reference to the accompanying Figures, in which some, but not all embodiments of the inventions are shown. Like numbers refer to like elements throughout. The presently disclosed subject matter may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements. Indeed, many modifications and other embodiments of the presently disclosed subject matter set forth herein will come to mind to one skilled in the art to which the presently disclosed subject matter pertains having the benefit of the teachings presented in the foregoing descriptions and the associated Figures. Therefore, it is to be understood that the presently disclosed subject matter is not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims.
I. Peptide/Particle Delivery Systems
The presently disclosed subject matter provides compositions of matter, methods of formulation, and methods of treatment utilizing drug delivery systems comprising one or more degradable polymers and one or more biological agents. The polymers described in these systems must be biodegradable. Mechanisms for this degradability include, but are not limited to, hydrolytic degradation, enzymatic degradation, and disulfide reduction. The biological agents described in these systems include, but are not limited to, therapeutic or diagnostic agents, such as small molecules, peptides, proteins, DNA, siRNA, miRNA, is RNA, contrast agents, and other agents one skilled in the field would wish to encapsulate. In particular embodiments, biological therapeutic agents that are sensitive to degradation and sized approximately 10,000-25,000 Da, including siRNA and peptides, are suitable for use with the presently disclosed materials.
Peptide drugs in polymeric delivery systems are useful for various therapeutic and diagnostic applications. Some embodiments of the presently disclosed subject matter are useful for treating angiogenesis-dependent diseases including, but not limited to, age-related macular degeneration (AMD) and cancer. One particular embodiment of the presently disclosed subject matter includes specific peptide sequences, as well as methods of formulating, stabilizing, and administering these peptides as single agents or as combinations of peptides via polymeric nanoparticle-based, microparticle-based, gel-based, or conjugate-based delivery systems.
The presently disclosed nanoparticles, microparticles, and gels can be used to deliver cargo, for example a therapeutic agent, such as a peptide or protein, to a target, for example, a cell. The cargo delivered by the presently disclosed nanoparticles, microparticles, and gels can act, in some embodiments, as a therapeutic agent or a biosensor agent. Combinations of polymeric materials and cargo, for example a single peptide or combination of peptides, can be formulated by the presently disclosed methods, which allows for the control, or tuning, of the time scale for delivery.
Further, the presently disclosed polymeric materials can be used to form self-assembled electrostatic complexes, micelles, polymersomes, emulsion-based particles, and other particle formulations known to one of ordinary skill in the art. Nanoparticles formed from the presently disclosed polymeric materials can be formulated into larger microparticles to further extend duration and timing of release. Lyophilized formulations that can maintain longer shelf life and stability also are described. The presently disclosed particles can be administered as a powder, cream, ointment, implant, or other reservoir device.
The presently disclosed nanoparticles, microparticles, and gels can be used to treat many diseases and conditions including, but not limited to, all types of cancers, ophthalmic diseases, cardiovascular diseases, and the like. In particular embodiments, the disease or condition treated by the presently disclosed nanoparticles, microparticles, and gels include breast cancer and age-related macular degeneration.
A. Bioreducible and Hydrolytically Degradable Two-Component Degradable Polymers
The presently disclosed materials offer several advantages for use in delivering cargo, e.g., a therapeutic agent, such as a peptide or siRNA, to a target, e.g., a cell. Such advantages include a slower degradation in the extracellular environment and a quicker degradation in the intracellular environment. Further, the method of synthesis allows for diversity of monomer starting materials and corresponding facile permutations of polymer structure. The presently disclosed materials can be used to form self-assembled nanoparticles, blended microparticles, gels, and bioconjugates. The presently disclosed polymers also have the following advantages compared to other drug delivery polymers known in the art: a higher polymerization than with disulfide acrylamides, which is important for various applications because it can be used to tune both binding/encapsulation and release; two time scales for degradation (hydrolytic degradation in water and disulfide reduction due to glutathione inside the cell), which facilitates drug release and reduces potential cytotoxicity; tunable structural diversity, with hydrophobic, hydrophilic, and charged moieties to aid in encapsulation of a target biological agent; and, usefulness for drug delivery, including high siRNA delivery, even without end-modification of the polymer.
Certain polyesters have been shown previously to form nanoparticles in the presence of biological agents, such as nucleic acids, and facilitate their entry into a cell. In such materials, release of the nucleic acid is modulated by hydrolytic degradation of the polyester polymer. The addition of a bioreducible disulfide moiety into the backbone of these polymers, however, can specifically target release to the reducing intracellular environment.
Accordingly, a library of bioreducible polyesters can be synthesized by oxidizing and acrylating various mercapto-alcohols (representative diacrylates formed from the presently disclosed synthetic process are shown in Scheme 1 below), then reacting with amine side chains. The structure of a representative bioreducible polyester, e.g., 2,2′-disulfanediylbis(ethane-2,1-diyl)diacrylate (BR6) polymerized with S4, also is shown in Scheme 1.




In other embodiments, amine-containing molecules can be reacted to terminal groups of the polymer. In particular embodiments, this amine-containing molecule also contains poly(ethylene glycol) (PEG) or a targeting ligand. In other embodiments, the disulfide acrylates are not reacted with amines, but are instead polymerized through other mechanisms including, but not limited to, free radical polymerization to form network polymers and gels. In other embodiments, oligomers are first formed and then the oligomers are polymerized to form block co-polymers or gels.
More particularly, the presently disclosed subject matter provides a bioreducible, hydrolytically degradable polymer of formula (Ia):




wherein:

n is an integer from 1 to 10,000;
R1, R2, R3, R4, R5, R6, R7, R8, and R9 are each independently selected from the group consisting of hydrogen, branched and unbranched alkyl, branched and unbranched alkenyl, branched and unbranched alkynyl, aryl, halogen, hydroxyl, alkoxy, carbamoyl, carboxyl ester, carbonyldioxyl, amide, thiohydroxyl, alkylthioether, amino, alkylamino, dialkylamino, trialkylamino, cyano, ureido, a substituted alkanoyl group, cyclic, cyclic aromatic, heterocyclic, and aromatic heterocyclic groups, each of which may be substituted with at least one substituent selected from the group consisting of branched or unbranched alkyl, branched and unbranched alkenyl, branched and unbranched alkynyl, amino, alkylamino, dialkylamino, trialkylamino, aryl, ureido, heterocyclic, aromatic heterocyclic, cyclic, aromatic cyclic, halogen, hydroxyl, alkoxy, cyano, amide, carbamoyl, carboxylic acid, ester, carbonyl, carbonyldioxyl, alkylthioether, and thiohydroxyl groups;
wherein R1 can be present or absent and when present the compound of formula (I) further comprises a counter ion selected from the group consisting of chloride, fluoride, bromide, iodide, sulfate, nitrate, fumarate, acetate, carbonate, stearate, laurate, and oleate; and
wherein at least one R comprises a backbone of a diacrylate having the following structure:




wherein X1 and X2 are each independently substituted or unsubstituted C2-C20 alkylene, and wherein each X1 and X2 can be the same or different.
In some embodiments, the bioreducible, hydrolytically degradable polymer of claim 1, wherein at least one R comprises a backbone of a diacrylate selected from the group consisting of:




or co-oligomers comprising combinations thereof, wherein the diacrylate can be the same or different.

Additional R, R′, and R′′ groups are defined immediately herein below as for compounds disclosed in International PCT Patent Application Publication No. WO/2010/132879 for “Multicomponent Degradable Cationic Polymers,” to Green et al., which is incorporated herein by reference in its entirety.
B. Hydrolytic and Bioreducible Polymeric Particle Formulations for Delivery of Peptides.
Multicomponent degradable cationic polymers suitable for the delivery of peptides to a target are disclosed in International PCT Patent Application Publication No. WO/2010/132879 for “Multicomponent Degradable Cationic Polymers,” to Green et al., which is incorporated herein by reference in its entirety. Such polymers, in addition to the presently disclosed polymers can be used to deliver cargo, e.g., a therapeutic agent, to a target, e.g., a cell.
In some embodiments, the presently disclosed subject matter generally provides multicomponent degradable cationic polymers. In some embodiments, the presently disclosed polymers have the property of biphasic degradation. Modifications to the polymer structure can result in a change in the release of therapeutic agents, which can occur over multiple time scales. In some embodiments, the presently disclosed polymers include a minority structure, e.g., an endcapping group, which differs from the majority structure comprising most of the polymer backbone. In other embodiments, the bioreducible oligomers form block copolymers with hydrolytically degradable oligomers. In yet other embodiments, the end group/minority structure comprises an amino acid or chain of amino acids, while the backbone degrades hydrolytically and/or is bioreducible.
As described in more detail herein below, small changes in the monomer ratio used during polymerization, in combination with modifications to the chemical structure of the end-capping groups used post-polymerization, can affect the efficacy of delivery of a therapeutic agent to a target. Further, changes in the chemical structure of the polymer, either in the backbone of the polymer or end-capping groups, or both, can change the efficacy of target delivery to a cell. In some embodiments, small changes to the molecular weight of the polymer or changes to the endcapping groups of the polymer, while leaving the main chain, i.e., backbone, of the polymer the same, can enhance or decrease the overall delivery of the target to a cell. Further, the “R” groups that comprise the backbone or main chain of the polymer can be selected to degrade via different biodegradation mechanisms within the same polymer molecule. Such mechanisms include, but are not limited to, hydrolytic, bioreducible, enzymatic, and/or other modes of degradation.
In some embodiments, the presently disclosed compositions can be prepared according to Scheme 2:




In some embodiments, at least one of the following groups R, R′, and R′′ contain reducible linkages and, for many of the presently disclosed materials, additional modes of degradation also are present. More generally, R′ can be any group that facilitates solubility in water and/or hydrogen bonding, for example, OH, NH, and SH. Representative degradable linkages include, but are not limited to:




The end group structures, i.e., R′′ groups in Scheme 2, for the presently disclosed cationic polymers are distinct and separate from the backbone structures (R) structures, the side chain structures (R′), and end group structures of the intermediate precursor molecule for a given polymeric material.
More particularly, in some embodiments, the presently disclosed subject matter includes a nanoparticle, microparticle, or gel comprising a compound of formula (I):




wherein:

n is an integer from 1 to 10,000;
R1, R2, R3, R4, R5, R6, R7, R8, and R9 are each independently selected from the group consisting of hydrogen, branched and unbranched alkyl, branched and unbranched alkenyl, branched and unbranched alkynyl, aryl, halogen, hydroxyl, alkoxy, carbamoyl, carboxyl ester, carbonyldioxyl, amide, thiohydroxyl, alkylthioether, amino, alkylamino, dialkylamino, trialkylamino, cyano, ureido, a substituted alkanoyl group, cyclic, cyclic aromatic, heterocyclic, and aromatic heterocyclic groups, each of which may be substituted with at least one substituent selected from the group consisting of branched or unbranched alkyl, branched and unbranched alkenyl, branched and unbranched alkynyl, amino, alkylamino, dialkylamino, trialkylamino, aryl, ureido, heterocyclic, aromatic heterocyclic, cyclic, aromatic cyclic, halogen, hydroxyl, alkoxy, cyano, amide, carbamoyl, carboxylic acid, ester, carbonyl, carbonyldioxyl, alkylthioether, and thiohydroxyl groups;
wherein R1 can be present or absent and when present the compound of formula (I) further comprises a counter ion selected from the group consisting of chloride, fluoride, bromide, iodide, sulfate, nitrate, fumarate, acetate, carbonate, stearate, laurate, and oleate; and
at least one of R, R′, and R′′ comprise a reducible or degradable linkage, and wherein each R, R′, or R′′ can independently be the same or different;
under the proviso that when at least one R group comprises an ester linkage of the formula —C(═O)—O— and the compound of formula (I) comprises a poly(beta-amino ester), then the compound of formula (I) must also comprise one or more of the following characteristics:
(a) each R group is different;
(b) each R′′ group is different;
(c) each R′′ group is not the same as any of R′, R1, R2, R3, R4, R5, R6, R7, R9, and R9;
(d) the R′′ groups degrade through a different mechanism than the ester-containing R groups, wherein the degradation of the R′′ group is selected from the group consisting of a bioreducible mechanism or an enzymatically degradable mechanism; and/or
(e) the compound of formula (I) comprises a substructure of a larger cross-linked polymer, wherein the larger cross-linked polymer comprises different properties from compound of formula (I);
and one or more peptides selected from the group consisting of an anti-angiogenic peptide, an anti-lymphangiogenic peptide, an anti-tumorigenic peptide, and an anti-permeability peptide.
In some embodiments of the nanoparticle, microparticle, or gel n is an integer from 1 to 1,000; in some embodiments, n is an integer from 1 to 100; in some embodiments, n is an integer from 1 to 30; in some embodiments, n is an integer from 5 to 20; in some embodiments, n is an integer from 10 to 15; and in some embodiments, n is an integer from 1 to 10.
In particular embodiments, the reducible or degradable linkage comprising R, R′, and R′′ is selected from the group consisting of an ester, a disulfide, an amide, an anhydride or a linkage susceptible to enzymatic degradation, subject to the proviso provided hereinabove.
In more particular embodiments, R comprises a backbone of a diacrylate selected from the group consisting of:







In some embodiments, wherein R′ comprises a side chain derived from compound selected from the group consisting of:




In some embodiments, R′′ comprises an end group derived from a compound selected from the group consisting of




In other embodiments, the compound of formula (I) is subject to the further proviso that if at least one R group comprises an ester linkage, then the R′′ groups impart one or more of the following characteristics to the compound of formula (I): independent control of cell-specific uptake and/or intracellular delivery of a particle; independent control of endosomal buffering and endosomal escape; independent control of DNA release; triggered release of an active agent; modification of a particle surface charge; increased diffusion through a cytoplasm of a cell; increased active transport through a cytoplasm of a cell; increased nuclear import within a cell; increased transcription of an associated DNA within a cell; increased translation of an associated DNA within a cell; increased persistence of an associated therapeutic agent within a cell, wherein the therapeutic agent is selected from the group consisting of DNA, RNA, a peptide or a protein.
More particularly, any poly(beta-amino ester) specifically disclosed or claimed in U.S. Pat. Nos. 6,998,115; 7,427,394; U.S. patent application publication no. US2005/0265961; and U.S. patent publication no. US2010/0036084, each of which is incorporated herein by reference in its entirety, is explicitly excluded from the presently disclosed compounds of formula (I). In particular, the poly(beta-amino ester)s disclosed in U.S. Pat. Nos. 6,998,115; 7,427,394; U.S. patent application publication no. US2005/0265961; and U.S. patent publication no. US2010/0036084 are symmetrical, i.e., both R groups as defined in formula (I) herein are the same. In certain embodiments of the presently disclosed compounds of formula (I), when at least one R comprises an ester linkage, the two R groups of formula (I) are not the same, i.e., in such embodiments, the compounds of formula (I) are not symmetrical.
In particular embodiments, the reducible or degradable linkage comprising R, R′, and R′′ is selected from the group consisting of an ester, a disulfide, an amide, an anhydride or a linkage susceptible to enzymatic degradation, subject to the above-mentioned provisos.
Further, in some embodiments of the compound of formula (I), n is an integer from 1 to 1,000; in other embodiments, n is an integer from 1 to 100; in other embodiments, n is an integer from 1 to 30; in other embodiments, n is an integer from 5 to 20; in other embodiments, n is an integer from 10 to 15; and in other embodiments, n is an integer from 1 to 10.
In some embodiments, R′′ can be an oligomer as described herein, e.g., one fully synthesized primary amine-terminated oligomer, and can be used as a reagent during the second reaction step of Scheme 2. This process can be repeated iteratively to synthesize increasingly complex molecules.
In other embodiments, R′′ can comprise a larger biomolecule including, but not limited to, poly(ethyleneglycol) (PEG), a targeting ligand, including, but not limited to, a sugar, a small molecule, an antibody, an antibody fragment, a peptide sequence, or other targeting moiety known to one skilled in the art; a labeling molecule including, but not limited to, a small molecule, a quantum dot, a nanoparticle, a fluorescent molecule, a luminescent molecule, a contrast agent, and the like; and a branched or unbranched, substituted or unsubstituted alkyl chain.
In some embodiments, the branched or unbranched, substituted or unsubstituted alkyl chain is about 2 to about 5 carbons long; in some embodiments, the alkyl chain is about 6 to about 8 carbons long; in some embodiments, the alkyl chain is about 9 to about 12 carbons long; in some embodiments, the alkyl chain is about 13 to about 18 carbons long; in some embodiments, the alkyl chain is about 19 to about 30 carbons long; in some embodiments, the alkyl chain is greater than about 30 carbons long.
In certain embodiments, both R′′ groups, i.e., the end groups of the polymer, comprise alkyl chains. In other embodiments, only one R′′ group comprises an alkyl chain. In some embodiments, at least one alkyl chain is terminated with an amino (NH2) group. In other embodiments, the at least one alkyl chain is terminated with a hydroxyl (OH) group.
In some embodiments, the PEG has a molecular weight of about 5 kDa or less; in some embodiments, the PEG has a molecular weight of about 5 kDa to about 10 kDa; in some embodiments, the PEG has a molecular weight of about 10 kDa to about 20 kDa; in some embodiments, the PEG has a molecular weight of about 20 kDa to about 30 kDa; in some embodiments, the PEG is greater than 30 kDa. In certain embodiments, both R′′ groups comprise PEG. In other embodiments, only one R′′ group comprises PEG.
Further, in some embodiments, one R′′ group is PEG and the other R′′ group is a targeting ligand and/or labeling molecule as defined herein above. In other embodiments, one R′′ group is an alkyl chain and the other R′′ group is a targeting ligand and/or labeling molecule.
Representative monomers used to synthesize the presently disclosed cationic polymers include, but are not limited to, those provided immediately herein below. The presently disclosed subject matter is not limited to the representative monomers disclosed herein, but also includes other structures that one skilled in the art could use to create similar biphasic degrading cationic polymers. For each type of cargo, a particular biodegradable polymer can be tuned through varying the constituent monomers used to form the backbone (designated as “B” groups), side-chains (designated as “S” groups), and end-groups (designated as “E” groups) of the polymer.













In particular embodiments, as depicted in Scheme 4, the presently disclosed cationic polymers comprise a polyalcohol structure, i.e., the side chain represented by R′ in Scheme 2 comprises an alcohol.




In such embodiments, the end group structures (R′′) and the backbone structures (R) are defined as above and the side chain must contain at least one hydroxyl (OH) group.
In yet other embodiments, the presently disclosed cationic polymer comprises a specific poly(ester amine) structure with secondary non-hydrolytic modes of degradation. In such embodiments, the cationic polymer comprises a polyester that degrades through ester linkages (hydrolytic degradation) that is further modified to comprise bioreducible groups as end (R′′) groups.




Representative bioreducible end groups in such embodiments include, but are not limited to:





In some embodiments, the presently disclosed cationic polymer comprises a specific poly(ester amine alcohol) structure with secondary non-hydrolytic modes of degradation. In such embodiments, the cationic polymer comprises a specific structure where a polyester that degrades through ester linkages (hydrolytic degradation) is modified to contain bioreducible groups as end groups.




In yet other embodiments, the presently disclosed cationic polymer comprises a specific poly(amido amine) structure having disulfide linking groups in the polymer backbone and an independent, non-reducible amine contacting group at the terminal ends of the polymer.




In such embodiments, R1 and R2 are alkyl chains. In some embodiments, the alkyl chain is 1-2 carbons long; in some embodiments, the alkyl chain is 3-5 carbons long; in some embodiments, the alkyl chain is 6-8 carbons long; in some embodiments, the alkyl chain is 9-12 carbons long; in some embodiments, the alkyl chain is 13-18 carbons long; in some embodiments, the alkyl chain is 19-30 carbons long; and in some embodiments, the alkyl chain is greater than 30 carbons long
Suitable non-reducible amino R′′ groups for such embodiments include, but are not limited to:
















In other embodiments, the presently disclosed cationic polymers comprise a specific poly(amido amine alcohol) structure having disulfide linking groups in the polymer backbone and an independent non-reducible amine contacting group at the terminal ends of the polymer.




In yet other embodiments, the presently disclosed cationic polymer comprises a copolymer of representative oligomers as described hereinabove. Such embodiments include, but are not limited to, a poly(amido amine) structure having disulfides in the polymer backbone and an independently degradable (non-reducible) group at least one end of the polymer. Such embodiments also include using a cross-linker to add bioreducible linkages to hydrolytically degradable materials and also provide for higher molecular weight materials. A representative example of this embodiment, along with suitable monomers is as follows:




In particular embodiments, the presently disclosed polymer is selected from the group consisting of:













Further aspects of the presently disclosed subject matter include: (a) the R substituent groups that make up the presently disclosed polymers degrade via different biodegradation mechanisms within the same polymer. These biodegradation mechanisms can include hydrolytic, bioreducible, enzymatic, and/or other modes of degradation; (b) the ends of the polymer include a minority structure that differs from the majority structure that comprises most of the polymer backbone; (c) in several embodiments, the side chain molecules contain hydroxyl (OH)/alcohol groups.
In some embodiments: (a) the backbone is bioreducible and the end groups of the polymer degrade hydrolytically; (b) the backbone degrades hydrolytically and the end groups are bioreducible; and (c) hydrolytically degradable oligomers are cross-linked with a bioreducible cross-linker; (d) bioreducible oligomers form block copolymers with hydrolytically degradable oligomers; and (e) the end group/minority structure comprises an amino acid or chain of amino acids, whereas the backbone degrades hydrolytically and/or is bioreducible.
One way to synthesize the presently disclosed materials is by the conjugate addition of amine-containing molecules to acrylates or acrylamides. This reaction can be done neat or in a solvent, such as DMSO or THF. Reactions can take place at a temperature ranging from about room temperature up to about 90° C. and can have a duration from about a few hours to about a few weeks. The presently disclosed methods can be used to create linear or branched polymers. In some embodiments, the molecular weight (MW) has a range from about 1 kDa to about 5 kDa, in other embodiments, the MW has a range from about 5 kDa to about 10 kDa, in other embodiments the MW has a range from about 10 kDa to about 15 kDa, in other embodiments, the MW has a range from about 15 kDa to about 25 kDa, in other embodiments, the MW has a range from about 25 kDa to about 50 kDa, and in other embodiments, the MW has a range from about 50 kDa to about 100 kDa. In other embodiments, the polymer forms a network, gel, and/or scaffold of apparent molecular weight greater than 100 kDa.
In particular embodiments, the presently disclosed subject matter provides hydrolytic and bioreducible polymeric particle formulations for the delivery of one or more peptides to a target. In some embodiments of the presently disclosed formulations, the particles are nanoparticles and, in other embodiments, they are microparticles. Some applications are to cancer and others are to ophthalmic diseases.
Accordingly, in some embodiments, the presently disclosed approach includes degradable nanoparticles, microparticles, and gels that release a peptide, which is capable of therapeutic activity through multiple modes of action. The presently disclosed peptides can simultaneously inhibit: (1) endothelial cell proliferation; (2) endothelial cell adhesion, (3) endothelial cell migration, (4) tumor cell proliferation, (5) tumor cell adhesion, and (6) tumor cell migration.
When combined with such peptides, the presently disclosed nanoparticles, microparticles, and gels: (1) protect and increase the persistence of the peptides that would otherwise be rapidly cleared in vivo; (2) allow passive targeting of tumor vasculature via nanoparticle biophysical properties to enable enhanced efficacy at the target site of action; (3) enable extended peptide release and minimized dosing schedules for affected patients; and (4) facilitate a continuous peptide concentration rather than a pulsatile profile that would be caused by bolus injections and fast clearance.
The presently disclosed microparticles have similar benefits to the nanoparticles except that they also persist longer and have an easier route for clinical administration. On the other hand, another advantage of the presently disclosed nanoparticles is that they are better able to passively target the peptides to tumor vasculature than are the microparticles. Representative embodiments of the presently disclosed microparticles are provided in Example 10, herein below.
Further, in some embodiments, one or more peptides, which can be the same or different, can be combined, e.g., encapsulated, directly or individually into different nanoparticles that then can be combined into the same microparticles.
C. Biodegradable Nanoparticles for Sustained Peptide Delivery
Selected polymers are able to encapsulate selected peptides possessing varied chemical properties. Changes to polymer structure, including small changes to the ends of the polymer only, can vary biophysical properties of these particles. These properties can be important to tune for effective in vivo peptide delivery. A small subset of the potential polymer library was screened to measure the effect of encapsulating the antiangiogenic peptides chemokinostatin-1 and pentastatin-1 within polymeric particles compared to unencapsulated, free peptides. Polymeric encapsulation of peptides enhanced the ability of the peptides to inhibit the proliferation of endothelial cells. An example of representative polymers encapsulating peptides is provided in Scheme 5.



















Theor.



Name
Sequence
pI
MW


















DEAH box poly8
EIELVEEEPPF
3.51
1330.45


(“DEAH” disclosed
(SEQ ID NO: 2485)




as SEQ





ID NO: 2484)





 


Wispostatin-1
SPWSPCSTSCGLGVS
7.80
1838.08



TRI





(SEQ ID NO: 2360)




 


Pentastatin
LRRFSTMPFMFCNI
9.02
2454.93



NNVCNF





(SEQ ID NO: 2375)




 


Chemokinostatin
NGRKACLNPASPIV
10.03
2625.19



KKIIEKMLNS





(SEQ ID NO: 2388)









In other embodiments, particles synthesized and composed as described above are then used as a “core” inner particle for future coatings to create multi-component (also referred to herein as multi-layer) particles. For other embodiments, other nanoparticles are used as cores, such as an inorganic nanoparticles (like gold) or soft polymeric nanoparticles, for example, as disclosed in International PCT Patent Application Publication No. WO/2010/132879 for “Multicomponent Degradable Cationic Polymers,” to Green et al., which is incorporated herein by reference in its entirety. In each embodiment, the core particle is then coated with charged polymers as described above, peptides as described above, and other biological agents. Exemplary embodiments of multilayer particles are illustrated in FIG. 1.
Layering can be mediated by electrostatic forces and alternate cationic and anionic layers can be used to incorporate additional peptides and biological agents. Polyelectrolytes, including degradable polymers and peptides, also are used to provide structure to the multilayers. Multilayers can release drugs, peptides, and biological agents from the particle due to hydrolytic degradation, enzyme activity, disulfide reduction, and/or diffusion.
D. Polymeric Gels for Controlled Release of Biological Agents.
i. Hydrogels (or “Organogels”) for Protein/Peptide Release
In some embodiments, the presently disclosed subject matter provides photocrosslinked gels for controlled release of cargo, including, but not limited to peptides and proteins. Such gels can be tuned for release of other drugs. In some embodiments, for example, as illustrated in FIG. 2, a solution of acrylate-terminated polymers is made using either acrylate-terminated polymers, such as poly(β-amino esters) (PBAEs), poly(ethylene glycol)diacrylate (PEGDA), small crosslinkers including, but not limited to, 1,4-butanediol diacrylate, or a mixture of the above. Because many of these materials are amphiphilic, a variety of solvents can be used, including water, PBS, and DMSO, to encapsulate drugs within them. Addition of a small amount (0.05% w/v) of photoinitiator and exposure to long-wave UV light for a period of time, e.g., 5-15 min at 1-3 mW, causes formation of a drug-loaded gel.
The gel swelling properties can vary with pH by taking advantage of the PBAE portions, which can be reversibly protonated. Changing ratios of PBAE to PEGDA and the addition of crosslinkers changes swelling properties by changing pore size or overall hydrophobicity. For example, doping in increasing amounts of a more hydrophobic PBAE (B4S4) into a network of hydrophilic PEGDA causes the release kinetics to slow when measuring protein release.
E. Stable Formulations
To increase stability of nanoparticles in suspension, especially with hydrolytically-degradable polymers, the presently disclosed subject matter provides a method of keeping DNA or other cargo stable and functional after storage. For example, freeze-drying often causes denaturation of biological molecules or irreversible aggregation and inactivation of nanoparticles. Referring now to FIG. 3, by adding sucrose as a lyoprotectant at a final concentration of, for example, 7.5-45 mg/mL, the presently disclosed subject matter demonstrates that particles can be freeze dried and stored, for example, at 4° C. or −20° C. for extended periods, e.g., months, without significant change in physicochemical or biological properties. Certain formulations, when stored dry, also might be stable at ambient temperatures up to 40° C. Furthermore, the presently disclosed process allows particles to be prepared in advance and used much more easily in a clinical setting. The presently disclosed subject matter also demonstrates that particles can be concentrated in this way much more highly than would be possible with free polymer, which may be advantageous for dose adjustment in clinical or pre-clinical models.
F. Inclusion of Lyophilized Nanoparticles into Pellets/Scaffolds for Long-Term Delivery
The presently disclosed nanoparticles can be stored in a dry form and can be used in gene delivery via three-dimensional (3D) constructs. While DNA is used as a cargo in this example, other cargos of interest to one skilled in the art including, but not limited to, siRNA, peptides, protein, imaging agents, and the like, can be used, as well. In other embodiments, DNA-loaded nanoparticles were incorporated into natural and synthetic scaffolds, disks, microparticles, and hydrogels for various potential applications.
G. Methods of Treating Angiogenesis-Dependent Diseases
Although significant progress has been made in treating angiogenesis-dependent diseases, such as cancers, major challenges remain in terms of development of drug resistance, metastasis and overall survival rates. Studies designed to decipher the modes of drug resistance have revealed that tumors are very versatile and use multiple pathways to continue to survive and metastasize. See Chiang A C, Massague J. Molecular basis of metastasis. N Engl J Med 2008;359(26):2814-23; Gupta G P, Massague J. Cancer metastasis: building a framework. Cell 2006;127(4):679-95. Resistance has been observed for both cytotoxic and antiangiogenic agents. Thus, multimodal therapeutic design emerges as a promising, and perhaps even a mandatory strategy for treatment of cancer. See Sawyers C L. Cancer: mixing cocktails. Nature 2007;449(7165):993-6; Dorrell M I, Aguilar E, Scheppke L, Barnett F H, Friedlander M. Combination angiostatic therapy completely inhibits ocular and tumor angiogenesis. Proc Natl Acad Sci USA 2007;104(3):967-72.
The key attributes of tumor growth and metastasis are: angiogenesis, which facilitates the supply of the growing tumor with oxygen and nutrients; lymphangiogenesis, which facilitates the spreading of cancer cells through the lymphatics; and cancer cell proliferation. Angiogenesis, in particular, plays a critical role in the growth of tumors and antiangiogenic therapies have the potential to treat cancer, either alone or in combination with conventional chemotherapies, by starving tumors of oxygen and nutrients. There is a need, however, to find more potent anti-cancer therapeutics, including antiangiogenic therapeutics, as well as delivery systems for these therapeutics. The presently disclosed subject matter can address all of these attributes in a combined system.
Many forms of cancer, including breast cancer, are dependent on angiogenesis, the growth of blood vessels. There is a great medical need for the development of a safe, effective, and inexpensive means of antiangiogenic therapy. One promising approach is the use of antiangiogenic peptides as the active agents. In some embodiments, the presently disclose'd subject matter provides peptides derived from several classes of proteins that are effective at preventing angiogenesis. In other embodiments, the presently disclosed subject matter provides other peptides that are able to inhibit cancer through additional mechanisms including, but not limited to, antilymphangiogenesis and apoptosis. In their current form, however, all of these peptides have a short in vivo half-life and they are not suitable for systemic administration or for long-term action. Thus, there is a need to package, protect, and deliver these peptides in a more stable, sustained fashion.
Accordingly, the presently disclosed biomaterials facilitate delivery of combinations of these peptides in an engineered fashion to synergistically kill cancer or treat other diseases, in particular, other angiogenesis-dependent diseases. More particularly, the presently disclosed subject matter provides an effective array of safe, biodegradable polymers for use in forming peptide-containing nanoparticles, microparticles, gels, and conjugates. The presently disclosed biomaterials can be used to construct particles, gels, and conjugates that vary in their biophysical properties and in biological properties, such as tumor accumulation and peptide release.
The presently disclosed formulations work through one or more of the following mechanisms: antiangiogenesis; inhibition of human endothelial cell proliferation and migration; inhibition of lymphatic endothelial cell proliferation and migration; and promotion of cancer apoptosis, as well as other mechanisms. The presently disclosed materials and methods can safely, effectively, and relatively inexpensively treat age-related macular degeneration (AMD), cancer, and other diseases.
Further, siRNA is a promising technology to silence the activity of many biological targets in many diseases including cancer, cardiovascular diseases, infectious diseases, neurological diseases, ophthalmic diseases, and others. In some cases, siRNA can be used to reach previously undruggable targets. The method of delivery and examples described herein for siRNA delivery apply equally to other similar RNA molecules including, but not limited to is RNA, agRNA, saRNA, and miRNA.
H. Nanoparticle-Mediated Multimodal Peptide Delivery
Conventional anti-angiogenesis treatments have proven to be very expensive with limited clinical success, particularly in breast cancer. The presently disclosed strategy combines more effective and multimodal therapeutic agents with nanomedicine to provide a delivery system to enhance their therapeutic effect. More particularly, the presently disclosed subject matter provides a single system that incorporates multimodal therapeutic activity, including, but not limited to, antiangiogenic activity, antilymphangiogenic activity, and apoptotic activity, and can be effective in limiting both tumor growth and metastasis.
Generally, small peptides possess many advantageous characteristics as therapeutic agents, including high specificity and low toxicity. Reichert J. Development trends for peptide therapeutics. Tufts Center for the Study of Drug Development 2008 . The main disadvantage of small peptides as therapeutic agents, however, is their short half-life. The presently disclosed subject matter capitalizes on the advantages of peptide agents by developing novel antiangiogenic, antilymphangiogenic, and apoptotic peptides targeting multiple pathways, and overcoming the disadvantages by designing a multi-agent nanocarrier system.
Approximately 25 peptides have been approved by the FDA, however, to date none of these approved peptides are antiangiogenic. Rosca E V, Koskimaki J E, Rivera C G, Pandey N B, Tamiz A P, Popel A S. Anti-angiogenic peptides for cancer therapeutics. Curr Pharm Biotechnol, 12(8):1101-1116 (2011). Several endogenous proteins/polypeptides, including angiostatin, endostatin, proteolytic fragments of collagen IV, pigment epithelium-derived factor, and thrombospondin, have antiangiogenic properties and can induce apoptosis in endothelial cells. Lucas R, Holmgren L, Garcia I, Jimenez B, Mandriota S J, Borlat F, et al. Multiple forms of angiostatin induce apoptosis in endothelial cells. Blood 1998; 92(12):4730-41. These proteins/polypeptides are large, however, and are not ideal for use as therapeutic agents. Further, full length human proteins, although theoretically not foreign to an individual's body, induce an immune response in some individuals.
More recently, a bioinformatics approach has allowed identification of candidate antiangiogenic regions of several proteins and synthetic peptides corresponding to those short sequences that possess the ability to suppress proliferation and migration of vascular endothelial cells in vitro and angiogenesis in vivo. Delivering such peptides to a cell and prolonging the duration of their activity, however, remains a challenge.
Although peptides are much easier to produce and are more scalable and less immunogenic than full-length proteins, they are eliminated from the body more quickly. The presently disclosed subject matter can increase and sustain residence time, increase accumulation in tumor vasculature, and maximize the therapeutic effects of such peptides. The presently disclosed subject matter combines biomaterial synthesis, sustained drug delivery, and anti-cancer peptide creation to provide nanoparticle-, microparticle-, and gel-based systems for sustained peptide delivery. The presently disclosed biodegradable biomaterials can be tuned for the encapsulation, protection, and sustained release of each type of peptide.
The use of the presently disclosed nanoparticles, microparticles, and gels limits toxicity because they can extravasate from the leaky neovasculature of the tumors and be trapped in the interstitium of the tumor once the anti-angiogenic compounds kill or normalize the vasculature. Further, the presently disclosed subject matter demonstrates that effective biomaterials for anti-cancer peptide nanoparticles, microparticles, and gels can be fabricated. Multiple anti-cancer peptides and other peptides can be combined within the same particle for multimodal peptide delivery, as well as multimodal therapy with other active agents including, but not limited to, other peptides, nucleic acids, proteins, small molecules, and the like.
More particularly, in some embodiments, the presently disclosed subject matter provides peptides that work through multiple biological mechanisms in combination with the presently disclosed biomaterials, including multilayer and multi-peptide nanoparticle formulations. An array of biodegradable polymers can be used to encapsulate peptides to create nanoparticles having varied biophysical properties and release kinetics. Each peptide can have a specialized subset of materials employed for its encapsulation. Referring now to FIG. 4, differing chemical structures can be synthesized by the conjugate addition of amines to acrylates or acrylamides of differing structure. The polymer structure can be tuned through variation to the backbone, side chain, end-group, hydrophobicity, and degradability. Unlike the polymeric materials disclosed in International PCT Patent Application Publication No. WO/2010/132879 for “Multicomponent Degradable Cationic Polymers,” to Green et al., which are cationic, i.e., positively charged, the presently disclosed polymers can be positively charged, whereas others can be negatively charged, others neutral and hydrophobic, and still others amphiphilic. The diversity of the presently disclosed biomaterials comes from the chemical diversity of the R groups (R, R′, R′′) in the biomaterial array and from parameter tuning during particle fabrication.
For example, to create the presently disclosed multi-peptide particles, hydrophobic core particles first are constructed by self-assembly, for example between the somatotropin-derived peptide, the collagen IV-derived peptide, and a hydrophobic polymer. These nanoparticles are then coated by charged biodegradable polymers and peptides following a particle coating and layer-by-layer technique that modifies techniques previously described. Green J J, Chiu E, Leshchiner E S, Shi J, Langer R, Anderson D G. Electrostatic ligand coatings of nanoparticles enable ligand-specific gene delivery to human primary cells. Nano Lett 2007;7(4):874-9; Shmueli R B, Anderson D G, Green J J. Electrostatic surface modifications to improve gene delivery. Expert Opin Drug Deliv 7(4):535-50. Through this process, the charged peptides (serpin-derived and chemokine-derived) can be incorporated into these multilayers. Charged biological agents, such as peptides and nucleic acids, can serve as both the therapeutic agent and the support polyelectrolyte in the presently disclosed systems.
In one embodiment, peptides can self-assemble with the presently disclosed polymers in an aqueous buffer due to physical, hydrophobic, and electrostatic forces. Zhang S, Uludag H. Nanoparticulate systems for growth factor delivery. Pharm Res 2009;26(7):1561-80. In other embodiments, peptide-containing micelles can be formed by synthetic polymer-mPEG (e.g., E15 from FIG. 4) block copolymers. Depending on formulation parameters, polymer/peptide particle sizes can be tuned from approximately 50 nm to approximately 500 nm.
As an alternative strategy for polymers in the library that are more hydrophobic or have higher glass transition temperatures, peptides can be encapsulated by a double emulsion procedure. In this method, droplets of aqueous buffer containing peptide are dispersed in the hydrophobic polymer phase and then the polymer phase is itself dispersed in another aqueous phase to form the polymeric particles. Jain R A. The manufacturing techniques of various drug loaded biodegradable poly(lactide-co-glycolide) (PLGA) devices. Biomaterials 2000;21(23):2475-90. As an alternative technique, blends of novel hydrophobic polymers and poly(lactic-co-glycolic acid) also can be made to form particles with unique degradation properties. Little S R, Lynn D M, Ge Q, Anderson D G, Puram S V, Chen J Z, et al. Poly-beta amino ester-containing microparticles enhance the activity of nonviral genetic vaccines. Proc Natl Acad Sci USA 2004;101(26):9534-9.
I. Peptides for Anti-angiogenesis, Anti-lymphangiogenesis, Anti-tumor, and Anti-permeability Activity.
Several classes of peptides have been developed that show either anti-proliferative or anti-migratory activity or both on endothelial cells. These peptides appear to function through distinct mechanisms of action and have been tested both in vitro and in vivo in tumor xenografts and in ocular mouse models. These peptides include a 24-mer peptide NGRKACLNPASPIVKKIIEKMLNS (SEQ ID NO: 2388) derived from the CXC chemokine protein GRO-α/CXCL1 and a collagen IV derived and modified 20-mer peptide LRRFSTMPFMF-Abu-NINNV-Abu-NF (SEQ ID NO: 2452) as a highly potent anti-proliferative and anti-migratory peptide targeting αvβ1 integrins on both endothelial and tumor cells; here Abu is the 2-Aminobutyric acid introduced in the sequence to facilitate translation to human.
An 11-mer anti-angiogenic peptide EIELVEEEPPF (SEQ ID NO: 2485) derived from the serpin domain of DEAH box polypeptide (“DEAH” disclosed as SEQ ID NO: 2484) also has been identified that shows significant inhibition of MDA-MB-231 tumor xenograft growth. A somatotropin family peptide LLRISLLLIESWLE (SEQ ID NO: 2483)(SP5033) derived from transmembrane45 protein that also has been identified and has anti-proliferative and anti-migratory activity on both endothelial cells and lymphatic endothelial cells. It is believed that this peptide is the first antilymphangiogenic peptide agent. Combining these peptides together can result in a peptide-based system that inhibits angiogenesis by several different mechanisms and also inhibits lymphangiogenesis that has been shown to promote tumor metastasis.
Representative peptides suitable for encapsulation with the presently disclosed biomaterials include those disclosed in International PCT Patent Application Publication Number WO2007/033215 A2 for “Compositions Having Antiangiogenic Activity and Uses Thereof,” to Popel et al., published Mar. 22, 2007; International PCT Patent Application Publication Number WO2008/085828 A2 for “Peptide Modulators of Angiogenesis and Use Thereof,” to Popel, published Jul. 17, 2008; U.S. Provisional Patent Application No. 61/421,706, filed Dec. 12, 2010, which is commonly owned; and U.S. Provisional Patent Application No. 61/489,500, filed May 24, 2011, which also is commonly owned, each of which is incorporated herein by reference in its entirety.
Accordingly, in some embodiments, peptide suitable for use in the presently disclosed subject matter are disclosed in Tables 1-10 of International PCT Patent Application Publication Number WO2008/085828 A2 for “Peptide Modulators of Angiogenesis and Use Thereof,” to Popel, published Jul. 17, 2008, which is incorporated herein by reference in its entirety.
Accordingly, in some embodiments, the presently disclosed subject matter provides a nanoparticle, microparticle, or gel comprising one or more peptides, wherein the one or more peptide is selected from the group consisting of an isolated peptide or analog thereof comprising one of the following amino acid sequences:









(SEQ ID NO: 2486)



TSP Motif: W-X(2)-C-X(3)-C-X(2)-G,


 



CXC Motif: G-X(3)-C-L


 



(SEQ ID NO: 2487)



Collagen Motif: C-N-X(3)-V-C


 



Collagen Motif: P-F-X(2)-C


 



(SEQ ID NO: 2488)



Somatotropin Motif: L-X(3)-L-L-X(3)-S-X-L


 



(SEQ ID NO: 2489)



Serpin Motif: L-X(2)-E-E-X-P






wherein X denotes a variable amino acid and the number in parentheses denotes the number of variable amino acids; W denotes tryptophan; C denotes cysteine, G denotes glycine, V denotes valine; L denotes leucine, P is proline, and wherein the peptide reduces blood vessel formation in a cell, tissue or organ.
In other embodiments, the the one or more peptide comprises an amino acid sequence shown in table 1-6, 8 and 9.
In other embodiments, the one or more peptide comprises an isolated peptide or analog thereof having at least 85% identity to an amino acid sequence shown in Table 1-10.
In other embodiments, the one or more peptide comprises an amino acid sequence shown in Table 1-10. In yet other embodiments, the one or more peptide consists essentially of an amino acid sequence shown in Table 1-10.
In particular embodiments, the one or more peptide comprises an isolated peptide or analog thereof comprising or consisting essentially of a sequence having at least 85% amino acid sequence identity to an amino acid sequence selected from the group consisting of:








Placental Lactogen
LLRISLLLIESWLE



(SEQ ID NO: 2483)


 


hGH-V
LLRISLLLTQSWLE



(SEQ ID NO: 2490)


 


GH2
LLHISLLLIQSWLE



(SEQ ID NO: 2491)


 


Chorionic somatomammotropin
LLRLLLLIESWLE



(SEQ ID NO: 2480)


 


Chorionic somatomammotropin
LLHISLLLIESRLE


hormone-like 1
(SEQ ID NO: 2482)


 


Transmembrane protein 45A
LLRSSLILLQGSWF



(SEQ ID NO: 2481)


 


IL-17 receptor C
RLRLLTLQSWLL



(SEQ ID NO: 2477)


 


Neuropeptide FF receptor 2
LLIVALLFILSWL



(SEQ ID NO: 2479)


 


Brush border myosin-I
LMRKSQILISSWF



(SEQ ID NO: 2478)






wherein the peptide reduces blood vessel formation in a cell, tissue or organ.

In yet more particular embodiments, the one or more peptide comprises an isolated peptide or analog thereof comprising or consisting essentially of a sequence having at least 85% amino acid sequence identity to an amino acid sequence selected from the group consisting of:










DEAH box polypeptide 8
EIELVEEEPPF



(“DEAH” disclosed as
(SEQ ID NO: 2485)



SEQ ID NO: 2484)



 



Caspase 10
AEDLLSEEDPF




(SEQ ID NO: 2492)


 



CKIP-1
TLDLIQEEDPS




(SEQ ID NO: 2493)






wherein the peptide reduces blood vessel formation in a cell, tissue or organ.

In further embodiments, the one or more peptide comprises an isolated peptide or analog thereof comprising or consisting essentially of a sequence having at least 85% amino acid sequence identity to an amino acid sequence selected from the group consisting of:








Collagen type IV, alpha6
LPRFSTMPFIYCNINEVCHY


fibril
(SEQ ID NO: 2494)






wherein the peptide reduces blood vessel formation in a cell, tissue or organ.








TABLE 1





The TSP-1 containing 20-mer with all the possible amino acid substitutions


(SEQ ID NO: 2495)
























AA#1
AA#2
AA#3
AA#4
AA#5
AA#6
AA#7
AA#8
AA#9
AA#10





























S
(9)
P
(13)
W
(29)
S
(14)
P
(9)
C
(29)
S
(26)
V
(7)
T
(15)
C
(29)


T
(9)
E
(5)


T
(5)
A
(5)


N
(2)
A
(6)
S
(10)




G
(6)
S
(3)


G
(5)
Q
(4)


T
(1)
R
(5)
R
(3)




Q
(2)
A
(2)


E
(2)
D
(3)




K
(4)
N
(1)




A
(1)
Q
(1)


D
(1)
E
(3)




G
(2)








K
(1)


R
(1)
K
(1)




S
(2)












A
(1)
R
(1)




T
(2)














V
(1)




E
(1)



















AA#11
AA#12
AA#13
AA#14
AA#15
AA#16
AA#17
AA#18
AA#19
AA#20





























G
(26)
G
(10)
G
(29)
V
(8)
Q
(11)
T
(10)
R
(26)
S
(5)
R
(15)
R
(1)


S
(2)
K
(4)


I
(4)
S
(7)
F
(4)
S
(2)
T
(5)
V
(1)




N
(1)
R
(4)


M
(3)
R
(6)
K
(3)
Q
(1)
V
(5)








M
(4)


T
(3)
K
(2)
Q
(3)


R
(3)








T
(2)


H
(2)
Y
(2)
S
(3)


H
(3)








L
(2)


A
(1)
A
(1)
L
(2)


E
(2)








D
(1)


E
(1)


E
(1)


Q
(2)








S
(1)


F
(1)


M
(1)


A
(1)








P
(1)


K
(1)


N
(1)


I
(1)












R
(1)


V
(1)
















S
(1)




















Q
(1)




















W
(1)




















Y
(1)
















TABLE 2







TSPs


Motif: W-X(2)-C-X(3)-C-X(2)-G


Number of Locations: 166


Number of Different Proteins: 54











SEQ
Accession
First
Last



ID
Number|Protein
Amino
Amino



NO:
Name
acid
acid
Sequence














1
O00622|CYR61_HUMAN
236
246
WsqCsktCgtG


 


2
O14514|BAI1_HUMAN
270
280
WgeCtrdCggG


 


3
O14514|BAI1_HUMAN
363
373
WsvCsstCgeG


 


4
O14514|BAI1_HUMAN
418
428
WslCsstCgrG


 


5
O14514|BAI1_HUMAN
476
486
WsaCsasCsqG


 


6
O14514|BAI1_HUMAN
531
541
WgsCsvtCgaG


 


7
O15072|ATS3_HUMAN
975
985
WseCsvtCgeG


 


8
O60241|BAI2_HUMAN
306
316
WsvCsltCgqG


 


9
O60241|BAI2_HUMAN
361
371
WslCsrsCgrG


 


10
O60241|BAI2_HUMAN
416
426
WgpCstsCanG


 


11
O60241|BAI2_HUMAN
472
482
WslCsktCdtG


 


12
O60242|BAI3_HUMAN
300
310
WstCsvtCgqG


 


13
O60242|BAI3_HUMAN
354
364
WslCsftCgrG


 


14
O60242|BAI3_HUMAN
409
419
WsqCsvtCsnG


 


15
O60242|BAI3_HUMAN
464
474
WsgCsksCdgG


 


16
O75173|ATS4_HUMAN
529
539
WgdCsrtCggG


 


17
O76076|WISP2_HUMAN
201
211
WgpCsttCglG


 


18
O95185|UNC5C_HUMAN
269
279
WsvCnsrCgrG


 


19
O95388|WISP1_HUMAN
223
233
WspCstsCglG


 


20
O95389|WISP3_HUMAN
216
226
WtpCsrtCgmG


 


21
O95450|ATS2_HUMAN
863
873
WspCskpCggG


 


22
O95450|ATS2_HUMAN
984
994
WsqCsvtCgnG


 


23
P07996|TSP1_HUMAN
388
398
WtsCstsCgnG


 


24
P07996|TSP1_HUMAN
444
454
WssCsvtCgdG


 


25
P07996|TSP1_HUMAN
501
511
WdiCsvtCggG


 


26
P13671|CO6_HUMAN
32
42
WtsCsktCnsG


 


27
P13671|CO6_HUMAN
75
85
WqrCpinCllG


 


28
P14222|PERF_HUMAN
374
384
WrdCsrpCppG


 


29
P27918|PROP_HUMAN
86
96
WapCsvtCseG


 


30
P27918|PROP_HUMAN
145
155
WepCsvtCskG


 


31
P27918|PROP_HUMAN
202
212
WtpCsasChgG


 


32
P29279|CTGF_HUMAN
206
216
WsaCsktCgmG


 


33
P35442|TSP2_HUMAN
390
400
WtqCsvtCgsG


 


34
P35442|TSP2_HUMAN
446
456
WssCsvtCgvG


 


35
P35442|TSP2_HUMAN
503
513
WsaCtvtCagG


 


36
P48745|NOV_HUMAN
213
223
WtaCsksCgmG


 


37
P49327|FAS_HUMAN
627
637
WeeCkqrCppG


 


38
P58397|ATS12_HUMAN
551
561
WshCsrtCgaG


 


39
P58397|ATS12_HUMAN
832
842
WteCsvtCgtG


 


40
P58397|ATS12_HUMAN
952
962
WseCsvsCggG


 


41
P58397|ATS12_HUMAN
1321
1331
WseCsttCglG


 


42
P58397|ATS12_HUMAN
1372
1382
WskCsrnCsgG


 


43
P58397|ATS12_HUMAN
1431
1441
WsqCsrsCggG


 


44
P58397|ATS12_HUMAN
1479
1489
WdlCstsCggG


 


45
P59510|ATS20_HUMAN
976
986
WsqCsrsCggG


 


46
P59510|ATS20_HUMAN
1031
1041
WseClvtCgkG


 


47
P59510|ATS20_HUMAN
1086
1096
WgpCtttCghG


 


48
P59510|ATS20_HUMAN
1162
1172
WtpCsvsCgrG


 


49
P59510|ATS20_HUMAN
1217
1227
WspCsasCghG


 


50
P59510|ATS20_HUMAN
1314
1324
WgsCsssCsgG


 


51
P59510|ATS20_HUMAN
1368
1378
WgeCsqtCggG


 


52
P59510|ATS20_HUMAN
1427
1437
WtsCsasCgkG


 


53
P59510|ATS20_HUMAN
1483
1493
WneCsvtCgsG


 


54
P59510|ATS20_HUMAN
1664
1674
WskCsvtCgiG


 


55
P82987|ATL3_HUMAN
84
94
WsdCsrtCggG


 


56
P82987|ATL3_HUMAN
427
437
WtaCsvsCggG


 


57
P82987|ATL3_HUMAN
487
497
WsqCtvtCgrG


 


58
P82987|ATL3_HUMAN
573
583
WsaCsttCgpG


 


59
P82987|ATL3_HUMAN
712
722
WgpCsatCgvG


 


60
P82987|ATL3_HUMAN
768
778
WqqCsrtCggG


 


61
P82987|ATL3_HUMAN
828
838
WskCsvsCgvG


 


62
P82987|ATL3_HUMAN
1492
1502
WsqCsvsCgeG


 


63
P82987|ATL3_HUMAN
1606
1616
WkpCtaaCgrG


 


64
Q13591|SEM5A_HUMAN
604
614
WspCsttCgiG


 


65
Q13591|SEM5A_HUMAN
662
672
WerCtaqCggG


 


66
Q13591|SEM5A_HUMAN
793
803
WsqCsrdCsrG


 


67
Q13591|SEM5A_HUMAN
850
860
WtkCsatCggG


 


68
Q496M8|CI094_HUMAN
259
269
WsaCtrsCggG


 


69
Q6S8J7|POTE8_HUMAN
27
37
WccCcfpCcrG


 


70
Q6UXZ4|UNC5D_HUMAN
261
271
WsaCnvrCgrG


 


71
Q6UY14|ATL4_HUMAN
53
63
WasCsqpCgvG


 


72
Q6UY14|ATL4_HUMAN
732
742
WtsCsrsCgpG


 


73
Q6UY14|ATL4_HUMAN
792
802
WsqCsvrCgrG


 


74
Q6UY14|ATL4_HUMAN
919
929
WgeCsseCgsG


 


75
Q6UY14|ATL4_HUMAN
979
989
WspCsrsCqgG


 


76
Q6ZMM2|ATL5_HUMAN
44
54
WtrCsssCgrG


 


77
Q76LX8|ATS13_HUMAN
1081
1091
WmeCsvsCgdG


 


78
Q86TH1|ATL2_HUMAN
56
66
WtaCsrsCggG


 


79
Q86TH1|ATL2_HUMAN
631
641
WseCsrtCgeG


 


80
Q86TH1|ATL2_HUMAN
746
756
WgpCsgsCgqG


 


81
Q86TH1|ATL2_HUMAN
803
813
WerCnttCgrG


 


82
Q86TH1|ATL2_HUMAN
862
872
WseCtktCgvG


 


83
Q8IUL8|CILP2_HUMAN
155
165
WgpCsgsCgpG


 


84
Q8IZJ1|UNC5B_HUMAN
255
265
WspCsnrCgrG


 


85
Q8N6G6|ATL1_HUMAN
42
52
WseCsrtCggG


 


86
Q8N6G6|ATL1_HUMAN
385
395
WtaCsssCggG


 


87
Q8N6G6|ATL1_HUMAN
445
455
WspCtvtCgqG


 


88
Q8TE56|ATS17_HUMAN
552
562
WsmCsrtCgtG


 


89
Q8TE56|ATS17_HUMAN
809
819
WegCsvqCggG


 


90
Q8TE56|ATS17_HUMAN
870
880
WspCsatCekG


 


91
Q8TE56|ATS17_HUMAN
930
940
WsqCsasCgkG


 


92
Q8TE56|ATS17_HUMAN
981
991
WstCsstCgkG


 


93
Q8TE57|ATS16_HUMAN
595
605
WspCsrtCggG


 


94
Q8TE57|ATS16_HUMAN
936
946
WsaCsrtCggG


 


95
Q8TE57|ATS16_HUMAN
995
1005
WaeCshtCgkG


 


96
Q8TE57|ATS16_HUMAN
1060
1070
WsqCsvtCerG


 


97
Q8TE57|ATS16_HUMAN
1135
1145
WsqCtasCggG


 


98
Q8TE58|ATS15_HUMAN
848
858
WgpCsasCgsG


 


99
Q8TE58|ATS15_HUMAN
902
912
WspCsksCgrG


 


100
Q8TE59|ATS19_HUMAN
642
652
WspCsrtCsaG


 


101
Q8TE59|ATS19_HUMAN
924
934
WedCdatCggG


 


102
Q8TE59|ATS19_HUMAN
985
995
WtpCsrtCgkG


 


103
Q8TE59|ATS19_HUMAN
1096
1106
WskCsitCgkG


 


104
Q8TE60|ATS18_HUMAN
598
608
WseCsrtCggG


 


105
Q8TE60|ATS18_HUMAN
940
950
WstCskaCagG


 


106
Q8TE60|ATS18_HUMAN
1000
1010
WsqCsktCgrG


 


107
Q8TE60|ATS18_HUMAN
1061
1071
WseCsatCglG


 


108
Q8TE60|ATS18_HUMAN
1132
1142
WqqCtvtCggG


 


109
Q8WXS8|ATS14_HUMAN
856
866
WapCskaCggG


 


110
Q8WXS8|ATS14_HUMAN
977
987
WsqCsatCgeG


 


111
Q92947|GCDH_HUMAN
225
235
WarCedgCirG


 


112
Q96RW7|HMCN1_HUMAN
4538
4548
WraCsvtCgkG


 


113
Q96RW7|HMCN1_HUMAN
4595
4605
WeeCtrsCgrG


 


114
Q96RW7|HMCN1_HUMAN
4652
4662
WgtCsesCgkG


 


115
Q96RW7|HMCN1_HUMAN
4709
4719
WsaCsvsCggG


 


116
Q96RW7|HMCN1_HUMAN
4766
4776
WgtCsrtCngG


 


117
Q96RW7|HMCN1_HUMAN
4823
4833
WsqCsasCggG


 


118
Q99732|LITAF_HUMAN
116
126
WlsCgslCllG


 


119
Q9C0I4|THS7B_HUMAN
49
59
WgrCtgdCgpG


 


120
Q9C0I4|THS7B_HUMAN
345
355
WspCsktCrsG


 


121
Q9C0I4|THS7B_HUMAN
746
756
WtpCprmCqaG


 


122
Q9C0I4|THS7B_HUMAN
1009
1019
WgsCsssCgiG


 


123
Q9C0I4|THS7B_HUMAN
1258
1268
WteCsqtCghG


 


124
Q9C0I4|THS7B_HUMAN
1381
1391
WstCeltCidG


 


125
Q9H324|ATS10_HUMAN
530
540
WgdCsrtCggG


 


126
Q9H324|ATS10_HUMAN
808
818
WtkCsaqCagG


 


127
Q9H324|ATS10_HUMAN
867
877
WslCsrsCdaG


 


128
Q9H324|ATS10_HUMAN
927
937
WseCtpsCgpG


 


129
Q9H324|ATS10_HUMAN
986
996
WgeCsaqCgvG


 


130
Q9HCB6|SPON1_HUMAN
510
520
WspCsisCgmG


 


131
Q9HCB6|SPON1_HUMAN
567
577
WdeCsatCgmG


 


132
Q9HCB6|SPON1_HUMAN
623
633
WsdCsvtCgkG


 


133
Q9HCB6|SPON1_HUMAN
677
687
WseCnksCgkG


 


134
Q9HCB6|SPON1_HUMAN
763
773
WseCtklCggG


 


135
Q9NS62|THSD1_HUMAN
349
359
WsqCsatCgdG


 


136
Q9P283|SEM5B_HUMAN
615
625
WalCstsCgiG


 


137
Q9P283|SEM5B_HUMAN
673
683
WskCssnCggG


 


138
Q9P283|SEM5B_HUMAN
804
814
WssCsrdCelG


 


139
Q9P283|SEM5B_HUMAN
861
871
WspCsasCggG


 


140
Q9P2N4|ATS9_HUMAN
1006
1016
WteCsksCdgG


 


141
Q9P2N4|ATS9_HUMAN
1061
1071
WseClvtCgkG


 


142
Q9P2N4|ATS9_HUMAN
1116
1126
WvqCsvtCgqG


 


143
Q9P2N4|ATS9_HUMAN
1191
1201
WtpCsatCgkG


 


144
Q9P2N4|ATS9_HUMAN
1247
1257
WssCsvtCgqG


 


145
Q9P2N4|ATS9_HUMAN
1337
1347
WgaCsstCagG


 


146
Q9P2N4|ATS9_HUMAN
1391
1401
WgeCtklCggG


 


147
Q9P2N4|ATS9_HUMAN
1450
1460
WssCsvsCgrG


 


148
Q9P2N4|ATS9_HUMAN
1506
1516
WsqCsvsCgrG


 


149
Q9P2N4|ATS9_HUMAN
1564
1574
WqeCtktCgeG


 


150
Q9P2N4|ATS9_HUMAN
1621
1631
WseCsvtCgkG


 


151
Q9P2N4|ATS9_HUMAN
1686
1696
WgsCsvsCgvG


 


152
Q9UHI8|ATS1_HUMAN
568
578
WgdCsrtCggG


 


153
Q9UHI8|ATS1_HUMAN
863
873
WgeCsksCelG


 


154
Q9UHI8|ATS1_HUMAN
917
927
WssCsktCgkG


 


155
Q9UKP4|ATS7_HUMAN
547
557
WsiCsrsCgmG


 


156
Q9UKP4|ATS7_HUMAN
924
934
WtkCtvtCgrG


 


157
Q9UKP5|ATS6_HUMAN
519
529
WgeCsrtCggG


 


158
Q9UKP5|ATS6_HUMAN
801
811
WseCsatCagG


 


159
Q9UNA0|ATS5_HUMAN
576
586
WgqCsrsCggG


 


160
Q9UNA0|ATS5_HUMAN
884
894
WlaCsrtCdtG


 


161
Q9UP79|ATS8_HUMAN
536
546
WgeCsrtCggG


 


162
Q9UP79|ATS8_HUMAN
842
852
WseCsstCgaG


 


163
Q9UPZ6|THS7A_HUMAN
203
213
WseCsktCgsG


 


164
Q9UPZ6|THS7A_HUMAN
780
790
WtsCpssCkeG


 


165
Q9UPZ6|THS7A_HUMAN
1044
1054
WsrCsksCgsG


 


166
Q9UPZ6|THS7A_HUMAN
1423
1433
WslCqltCvnG
















TABLE 3





The C-X-C chemokine 22-mer with all the possible amino acid substitutions


(SEQ ID NO: 2496)

























AA#1
AA#2
AA#3
AA#4
AA#5
AA#6
AA#7
AA#8
AA#9
AA#10
AA#11































N
(4)
G
(6)
R
(3)
K
(3)
A
(2)
C
(6)
L
(6)
D
(4)
P
(6)
A
(2)
A
(3)


D
(2)


K
(3)
E
(2)
I
(2)




N
(2)


E
(2)
S
(2)








Q
(1)
L
(1)








D
(1)
E
(1)










V
(1)








K
(1)






















AA#12
AA#13
AA#14
AA#15
AA#16
AA#17
AA#18
AA#19
AA#20
AA#21
AA#22































P
(6)
F
(2)
V
(3)
K
(4)
K
(5)
I
(3)
I
(4)
E
(3)
K
(6)
I
(3)
L
(6)




I
(1)
L
(2)
Q
(2)
R
(1)
V
(3)
V
(2)
Q
(3)


F
(1)






M
(1)
I
(1)












K
(1)






R
(1)














M
(1)






W
(1)


































TABLE 4







CXCs


Motif: G-X(3)-C-L


Number of Locations: 1337


Number of Different Proteins: 1170











SEQ
Accession
First
Last



ID
Number|Protein
Amino
Amino



NO:
Name
acid
acid
Sequence














167
O00142|KITM_HUMAN
62
67
GkttCL


 


168
O00167|EYA2_HUMAN
361
366
GanlCL


 


169
O00220|TR10A_HUMAN
332
337
GeaqCL


 


170
O00291|HIP1_HUMAN
699
704
GattCL


 


171
O00409|FOXN3_HUMAN
465
470
GirsCL


 


172
O00444|PLK4_HUMAN
775
780
GhriCL


 


173
O00462|MANBA_HUMAN
744
749
GeavCL


 


174
O00468|AGRIN_HUMAN
1549
1554
GdhpCL


 


175
O00468|AGRIN_HUMAN
2012
2017
GfvgCL


 


176
O00476|NPT4_HUMAN
144
149
GcvcCL


 


177
O00488|ZN593_HUMAN
41
46
GlhrCL


 


178
O00501|CLD5_HUMAN
10
15
GlvlCL


 


179
O00624|NPT3_HUMAN
220
225
GcvcCL


 


180
O14514|BAI1_HUMAN
243
248
GpenCL


 


181
O14522|PTPRT_HUMAN
736
741
GtplCL


 


182
O14548|COX7R_HUMAN
97
102
GtiyCL


 


183
O14617|AP3D1_HUMAN
1113
1118
GhhvCL


 


184
O14628|ZN195_HUMAN
51
56
GlitCL


 


185
O14772|FPGT_HUMAN
515
520
GnktCL


 


186
O14773|TPP1_HUMAN
2
7
GlqaCL


 


187
O14792|OST1_HUMAN
261
266
GrdrCL


 


188
O14817|TSN4_HUMAN
68
73
GfvgCL


 


189
O14841|OPLA_HUMAN
1240
1245
GdvfCL


 


190
O14842|FFAR1_HUMAN
166
171
GspvCL


 


191
O14894|T4S5_HUMAN
100
105
GaiyCL


 


192
O14981|BTAF1_HUMAN
608
613
GawlCL


 


193
O15021|MAST4_HUMAN
1534
1539
GsheCL


 


194
O15031|PLXB2_HUMAN
308
313
GaglCL


 


195
O15056|SYNJ2_HUMAN
27
32
GrddCL


 


196
O15060|ZBT39_HUMAN
272
277
GtnsCL


 


197
O15063|K0355_HUMAN
244
249
GcdgCL


 


198
O15067|PUR4_HUMAN
914
919
GlvtCL


 


199
O15067|PUR4_HUMAN
1040
1045
GpsyCL


 


200
O15084|ANR28_HUMAN
449
454
GnleCL


 


201
O15084|ANR28_HUMAN
549
554
GhrlCL


 


202
O15084|ANR28_HUMAN
661
666
GhseCL


 


203
O15105|SMAD7_HUMAN
293
298
GngfCL


 


204
O15146|MUSK_HUMAN
648
653
GkpmCL


 


205
O15229|KMO_HUMAN
320
325
GfedCL


 


206
O15230|LAMA5_HUMAN
1933
1938
GrtqCL


 


207
O15296|LX15B_HUMAN
157
162
GwphCL


 


208
O15305|PMM2_HUMAN
5
10
GpalCL


 


209
O15354|GPR37_HUMAN
448
453
GcyfCL


 


210
O15379|HDAC3_HUMAN
214
219
GryyCL


 


211
O15397|IPO8_HUMAN
148
153
GsllCL


 


212
O15554|KCNN4_HUMAN
263
268
GkivCL


 


213
O43156|K0406_HUMAN
642
647
GkdfCL


 


214
O43175|SERA_HUMAN
111
116
GmimCL


 


215
O43175|SERA_HUMAN
416
421
GfgeCL


 


216
O43184|ADA12_HUMAN
407
412
GmgvCL


 


217
O43283|M3K13_HUMAN
133
138
GlfgCL


 


218
O43396|TXNL1_HUMAN
32
37
GcgpCL


 


219
O43396|TXNL1_HUMAN
144
149
GfdnCL


 


220
O43405|COCH_HUMAN
10
15
GlgvCL


 


221
O43541|SMAD6_HUMAN
363
368
GsgfCL


 


222
O43609|SPY1_HUMAN
219
224
GtcmCL


 


223
O43638|FREA_HUMAN
315
320
GltpCL


 


224
O43747|AP1G1_HUMAN
65
70
GqleCL


 


225
O43820|HYAL3_HUMAN
12
17
GvalCL


 


226
O43837|IDH3B_HUMAN
181
186
GvieCL


 


227
O43889|CREB3_HUMAN
330
335
GntsCL


 


228
O60244|CRSP2_HUMAN
447
452
GnseCL


 


229
O60266|ADCY3_HUMAN
44
49
GsclCL


 


230
O60266|ADCY3_HUMAN
944
949
GgieCL


 


231
O60292|SI1L3_HUMAN
658
663
GekvCL


 


232
O60423|AT8B3_HUMAN
238
243
GdvvCL


 


233
O60504|VINEX_HUMAN
478
483
GehiCL


 


234
O60508|PRP17_HUMAN
320
325
GerrCL


 


235
O60613|SEP15_HUMAN
4
9
GpsgCL


 


236
O60656|UD19_HUMAN
510
515
GyrkCL


 


237
O60662|KBTBA_HUMAN
447
452
GmiyCL


 


238
O60669|MOT2_HUMAN
93
98
GllcCL


 


239
O60673|DPOLZ_HUMAN
47
52
GqktCL


 


240
O60704|TPST2_HUMAN
229
234
GkekCL


 


241
O60706|ABCC9_HUMAN
1046
1051
GiflCL


 


242
O60883|ETBR2_HUMAN
315
320
GcyfCL


 


243
O75037|KI21B_HUMAN
1454
1459
GpvmCL


 


244
O75037|KI21B_HUMAN
1617
1622
GltpCL


 


245
O75052|CAPON_HUMAN
420
425
GrrdCL


 


246
O75077|ADA23_HUMAN
487
492
GggaCL


 


247
O75078|ADA11_HUMAN
429
434
GggsCL


 


248
O75094|SLIT3_HUMAN
1428
1433
GepyCL


 


249
O75095|MEGF6_HUMAN
695
700
GaclCL


 


250
O75173|ATS4_HUMAN
19
24
GaqpCL


 


251
O75173|ATS4_HUMAN
419
424
GyghCL


 


252
O75311|GLRA3_HUMAN
387
392
GmgpCL


 


253
O75326|SEM7A_HUMAN
499
504
GchgCL


 


254
O75342|LX12B_HUMAN
299
304
GegtCL


 


255
O75342|LX12B_HUMAN
552
557
GfprCL


 


256
O75346|ZN253_HUMAN
131
136
GlnqCL


 


257
O75426|FBX24_HUMAN
119
124
GrrrCL


 


258
O75436|VP26A_HUMAN
169
174
GiedCL


 


259
O75443|TECTA_HUMAN
1687
1692
GdgyCL


 


260
O75445|USH2A_HUMAN
1668
1673
GfvgCL


 


261
O75445|USH2A_HUMAN
4401
4406
GqglCL


 


262
O75446|SAP30_HUMAN
64
69
GqlcCL


 


263
O75508|CLD11_HUMAN
164
169
GavlCL


 


264
O75569|PRKRA_HUMAN
268
273
GqyqCL


 


265
O75592|MYCB2_HUMAN
1087
1092
GfgvCL


 


266
O75636|FCN3_HUMAN
16
21
GgpaCL


 


267
O75678|RFPL2_HUMAN
117
122
GcavCL


 


268
O75679|RFPL3_HUMAN
56
61
GctvCL


 


269
O75689|CENA1_HUMAN
37
42
GvfiCL


 


270
O75691|UTP20_HUMAN
2132
2137
GalqCL


 


271
O75694|NU155_HUMAN
230
235
GkdgCL


 


272
O75843|AP1G2_HUMAN
67
72
GqmeCL


 


273
O75886|STAM2_HUMAN
42
47
GakdCL


 


274
O75911|DHRS3_HUMAN
168
173
GhivCL


 


275
O75916|RGS9_HUMAN
642
647
GsgtCL


 


276
O75923|DYSF_HUMAN
378
383
GahfCL


 


277
O75923|DYSF_HUMAN
1574
1579
GpqeCL


 


278
O75925|PIAS1_HUMAN
431
436
GvdgCL


 


279
O75954|TSN9_HUMAN
4
9
GclcCL


 


280
O75954|TSN9_HUMAN
68
73
GflgCL


 


281
O76000|OR2B3_HUMAN
108
113
GateCL


 


282
O76013|K1H6_HUMAN
58
63
GlgsCL


 


283
O76064|RNF8_HUMAN
15
20
GrswCL


 


284
O76075|DFFB_HUMAN
43
48
GsrlCL


 


285
O94759|TRPM2_HUMAN
272
277
GnltCL


 


286
O94759|TRPM2_HUMAN
713
718
GkttCL


 


287
O94761|RECQ4_HUMAN
543
548
GlppCL


 


288
O94779|CNTN5_HUMAN
169
174
GhyqCL


 


289
O94779|CNTN5_HUMAN
265
270
GsyiCL


 


290
O94779|CNTN5_HUMAN
454
459
GmyqCL


 


291
O94829|IPO13_HUMAN
159
164
GqgrCL


 


292
O94856|NFASC_HUMAN
312
317
GeyfCL


 


293
O94887|FARP2_HUMAN
192
197
GqqhCL


 


294
O94900|TOX_HUMAN
22
27
GpspCL


 


295
O94907|DKK1_HUMAN
107
112
GvqiCL


 


296
O94919|ENDD1_HUMAN
371
376
GiesCL


 


297
O94933|SLIK3_HUMAN
898
903
GfvdCL


 


298
O94955|RHBT3_HUMAN
386
391
GkinCL


 


299
O94956|SO2B1_HUMAN
449
454
GmllCL


 


300
O95071|EDD1_HUMAN
531
536
GtqvCL


 


301
O95153|RIMB1_HUMAN
79
84
GaeaCL


 


302
O95153|RIMB1_HUMAN
1485
1490
GlasCL


 


303
O95163|IKAP_HUMAN
472
477
GfkvCL


 


304
O95202|LETM1_HUMAN
43
48
GlrnCL


 


305
O95210|GET1_HUMAN
285
290
GdheCL


 


306
O95239|KIF4A_HUMAN
27
32
GcqmCL


 


307
O95248|MTMR5_HUMAN
159
164
GlnvCL


 


308
O95248|MTMR5_HUMAN
381
386
GyrwCL


 


309
O95255|MRP6_HUMAN
845
850
GalvCL


 


310
O95255|MRP6_HUMAN
943
948
GtplCL


 


311
O95255|MRP6_HUMAN
992
997
GllgCL


 


312
O95256|I18RA_HUMAN
447
452
GyslCL


 


313
O95279|KCNK5_HUMAN
122
127
GvplCL


 


314
O95294|RASL1_HUMAN
130
135
GqgrCL


 


315
O95342|ABCBB_HUMAN
327
332
GfvwCL


 


316
O95373|IPO7_HUMAN
147
152
GillCL


 


317
O95396|MOCS3_HUMAN
250
255
GvlgCL


 


318
O95405|ZFYV9_HUMAN
137
142
GnlaCL


 


319
O95477|ABCA1_HUMAN
2120
2125
GrfrCL


 


320
O95500|CLD14_HUMAN
178
183
GtllCL


 


321
O95551|TTRAP_HUMAN
217
222
GnelCL


 


322
O95602|RPA1_HUMAN
1556
1561
GitrCL


 


323
O95620|DUS4L_HUMAN
125
130
GygaCL


 


324
O95633|FSTL3_HUMAN
88
93
GlvhCL


 


325
O95671|ASML_HUMAN
588
593
GeyqCL


 


326
O95714|HERC2_HUMAN
717
722
GsthCL


 


327
O95714|HERC2_HUMAN
3265
3270
GalhCL


 


328
O95714|HERC2_HUMAN
4047
4052
GgkhCL


 


329
O95715|SCYBE_HUMAN
68
73
GqehCL


 


330
O95780|ZN682_HUMAN
132
137
GlnqCL


 


331
O95803|NDST3_HUMAN
815
820
GktkCL


 


332
O95858|TSN15_HUMAN
285
290
GtgcCL


 


333
O95873|CF047_HUMAN
171
176
GpeeCL


 


334
O95886|DLGP3_HUMAN
284
289
GgpfCL


 


335
O95967|FBLN4_HUMAN
76
81
GgylCL


 


336
O95977|EDG6_HUMAN
333
338
GpgdCL


 


337
O96006|ZBED1_HUMAN
221
226
GapnCL


 


338
O96008|TOM40_HUMAN
72
77
GacgCL


 


339
O96009|NAPSA_HUMAN
350
355
GvrlCL


 


340
P00505|AATM_HUMAN
268
273
GinvCL


 


341
P00750|TPA_HUMAN
515
520
GplvCL


 


342
P00751|CFAB_HUMAN
288
293
GakkCL


 


343
P01130|LDLR_HUMAN
314
319
GtneCL


 


344
P01133|EGF_HUMAN
741
746
GadpCL


 


345
P01266|THYG_HUMAN
2020
2025
GevtCL


 


346
P01375|TNFA_HUMAN
26
31
GsrrCL


 


347
P01730|CD4_HUMAN
366
371
GmwqCL


 


348
P01833|PIGR_HUMAN
437
442
GfywCL


 


349
P02775|SCYB7_HUMAN
101
106
GrkiCL


 


350
P02776|PLF4_HUMAN
37
42
GdlqCL


 


351
P02776|PLF4_HUMAN
79
84
GrkiCL


 


352
P02778|SCYBA_HUMAN
70
75
GekrCL


 


353
P02787|TRFE_HUMAN
209
214
GafkCL


 


354
P02787|TRFE_HUMAN
538
543
GafrCL


 


355
P02788|TRFL_HUMAN
213
218
GafkCL


 


356
P02788|TRFL_HUMAN
549
554
GafrCL


 


357
P03986|TCC_HUMAN
28
33
GtylCL


 


358
P04350|TBB4_HUMAN
235
240
GvttCL


 


359
P04920|B3A2_HUMAN
751
756
GvvfCL


 


360
P05108|CP11A_HUMAN
458
463
GvrqCL


 


361
P05141|ADT2_HUMAN
155
160
GlgdCL


 


362
P05549|AP2A_HUMAN
371
376
GiqsCL


 


363
P06401|PRGR_HUMAN
484
489
GasgCL


 


364
P06756|ITAV_HUMAN
905
910
GvaqCL


 


365
P07202|PERT_HUMAN
819
824
GgfqCL


 


366
P07339|CATD_HUMAN
362
367
GktlCL


 


367
P07357|CO8A_HUMAN
117
122
GdqdCL


 


368
P07437|TBB5_HUMAN
235
240
GvttCL


 


369
P07686|HEXB_HUMAN
483
488
GgeaCL


 


370
P07814|SYEP_HUMAN
261
266
GhscCL


 


371
P07942|LAMB1_HUMAN
1052
1057
GqclCL


 


372
P07988|PSPB_HUMAN
244
249
GicqCL


 


373
P08151|GLI1_HUMAN
14
19
GepcCL


 


374
P08151|GLI1_HUMAN
828
833
GlapCL


 


375
P08243|ASNS_HUMAN
8
13
GsddCL


 


376
P08319|ADH4_HUMAN
241
246
GatdCL


 


377
P08582|TRFM_HUMAN
212
217
GafrCL


 


378
P08582|TRFM_HUMAN
558
563
GafrCL


 


379
P08686|CP21A_HUMAN
424
429
GarvCL


 


380
P08697|A2AP_HUMAN
139
144
GsgpCL


 


381
P08709|FA7_HUMAN
14
19
GlqgCL


 


382
P08922|ROS_HUMAN
2248
2253
GdviCL


 


383
P09001|RM03_HUMAN
291
296
GhknCL


 


384
P09326|CD48_HUMAN
5
10
GwdsCL


 


385
P09341|GROA_HUMAN
81
86
GrkaCL


 


386
P09848|LPH_HUMAN
1846
1851
GphaCL


 


387
P10071|GLI3_HUMAN
1359
1364
GpesCL


 


388
P10109|ADX_HUMAN
151
156
GcqiCL


 


389
P10145|IL8_HUMAN
73
78
GrelCL


 


390
P10635|CP2D6_HUMAN
439
444
GrraCL


 


391
P10646|TFPI1_HUMAN
213
218
GpswCL


 


392
P10720|PF4V_HUMAN
40
45
GdlqCL


 


393
P10720|PF4V_HUMAN
82
87
GrkiCL


 


394
P10745|IRBP_HUMAN
328
333
GvvhCL


 


395
P11047|LAMC1_HUMAN
903
908
GqceCL


 


396
P11362|FGFR1_HUMAN
337
342
GeytCL


 


397
P11717|MPRI_HUMAN
231
236
GtaaCL


 


398
P12236|ADT3_HUMAN
155
160
GlgdCL


 


399
P13473|LAMP2_HUMAN
228
233
GndtCL


 


400
P13498|CY24A_HUMAN
45
50
GvfvCL


 


401
P13569|CFTR_HUMAN
124
129
GiglCL


 


402
P13686|PPA5_HUMAN
215
220
GpthCL


 


403
P13804|ETFA_HUMAN
49
54
GevsCL


 


404
P13807|GYS1_HUMAN
185
190
GvglCL


 


405
P13861|KAP2_HUMAN
354
359
GdvkCL


 


406
P14222|PERF_HUMAN
530
535
GggtCL


 


407
P14543|NID1_HUMAN
24
29
GpvgCL


 


408
P14867|GBRA1_HUMAN
6
11
GlsdCL


 


409
P15151|PVR_HUMAN
119
124
GnytCL


 


410
P15538|C11B1_HUMAN
446
451
GmrqCL


 


411
P15692|VEGFA_HUMAN
168
173
GarcCL


 


412
P16109|LYAM3_HUMAN
271
276
GnmiCL


 


413
P16112|PGCA_HUMAN
2183
2188
GhviCL


 


414
P16581|LYAM2_HUMAN
376
381
GymnCL


 


415
P17038|ZNF43_HUMAN
127
132
GfnqCL


 


416
P17040|ZNF31_HUMAN
184
189
GnsvCL


 


417
P17936|IBP3_HUMAN
66
71
GcgcCL


 


418
P18510|IL1RA_HUMAN
87
92
GgkmCL


 


419
P18564|ITB6_HUMAN
674
679
GeneCL


 


420
P18577|RHCE_HUMAN
306
311
GgakCL


 


421
P19099|C11B2_HUMAN
446
451
GmrqCL


 


422
P19224|UD16_HUMAN
512
517
GyrkCL


 


423
P19367|HXK1_HUMAN
713
718
GdngCL


 


424
P19835|CEL_HUMAN
96
101
GdedCL


 


425
P19875|MIP2A_HUMAN
81
86
GqkaCL


 


426
P19876|MIP2B_HUMAN
81
86
GkkaCL


 


427
P19883|FST_HUMAN
252
257
GgkkCL


 


428
P20062|TCO2_HUMAN
79
84
GyqqCL


 


429
P20273|CD22_HUMAN
691
696
GlgsCL


 


430
P20648|ATP4A_HUMAN
108
113
GglqCL


 


431
P20701|ITAL_HUMAN
76
81
GtghCL


 


432
P20701|ITAL_HUMAN
1150
1155
GdpgCL


 


433
P20813|CP2B6_HUMAN
432
437
GkriCL


 


434
P20916|MAG_HUMAN
301
306
GvyaCL


 


435
P20929|NEBU_HUMAN
4517
4522
GvvhCL


 


436
P21554|CNR1_HUMAN
427
432
GdsdCL


 


437
P21580|TNAP3_HUMAN
99
104
GdgnCL


 


438
P21802|FGFR2_HUMAN
5
10
GrfiCL


 


439
P21802|FGFR2_HUMAN
338
343
GeytCL


 


440
P21817|RYR1_HUMAN
840
845
GpsrCL


 


441
P21860|ERBB3_HUMAN
513
518
GpgqCL


 


442
P21964|COMT_HUMAN
30
35
GwglCL


 


443
P22064|LTB1S_HUMAN
938
943
GsfrCL


 


444
P22064|LTB1S_HUMAN
1359
1364
GsykCL


 


445
P22105|TENX_HUMAN
565
570
GrgqCL


 


446
P22309|UD11_HUMAN
276
281
GginCL


 


447
P22309|UD11_HUMAN
513
518
GyrkCL


 


448
P22310|UD14_HUMAN
514
519
GyrkCL


 


449
P22314|UBE1_HUMAN
230
235
GvvtCL


 


450
P22455|FGFR4_HUMAN
97
102
GrylCL


 


451
P22455|FGFR4_HUMAN
220
225
GtytCL


 


452
P22455|FGFR4_HUMAN
329
334
GeytCL


 


453
P22607|FGFR3_HUMAN
335
340
GeytCL


 


454
P22680|CP7A1_HUMAN
330
335
GnpiCL


 


455
P22732|GTR5_HUMAN
348
353
GfsiCL


 


456
P23142|FBLN1_HUMAN
269
274
GihnCL


 


457
P23142|FBLN1_HUMAN
547
552
GgfrCL


 


458
P23416|GLRA2_HUMAN
376
381
GmghCL


 


459
P23759|PAX7_HUMAN
466
471
GqseCL


 


460
P24386|RAE1_HUMAN
395
400
GgiyCL


 


461
P24557|THAS_HUMAN
475
480
GprsCL


 


462
P24592|IBP6_HUMAN
100
105
GrgrCL


 


463
P24593|IBP5_HUMAN
96
101
GrgvCL


 


464
P24821|TENA_HUMAN
143
148
GagcCL


 


465
P24903|CP2F1_HUMAN
432
437
GrrlCL


 


466
P25205|MCM3_HUMAN
239
244
GtyrCL


 


467
P25874|UCP1_HUMAN
21
26
GiaaCL


 


468
P25940|C05A3_HUMAN
1581
1586
GgetCL


 


469
P26374|RAE2_HUMAN
397
402
GgiyCL


 


470
P26951|IL3RA_HUMAN
363
368
GleeCL


 


471
P27487|DPP4_HUMAN
335
340
GrwnCL


 


472
P27540|ARNT_HUMAN
332
337
GskfCL


 


473
P27987|IP3KB_HUMAN
284
289
GtrsCL


 


474
P28332|ADH6_HUMAN
237
242
GateCL


 


475
P28340|DPOD1_HUMAN
709
714
GklpCL


 


476
P29274|AA2AR_HUMAN
162
167
GqvaCL


 


477
P29353|SHC1_HUMAN
570
575
GselCL


 


478
P29459|IL12A_HUMAN
33
38
GmfpCL


 


479
P30040|ERP29_HUMAN
153
158
GmpgCL


 


480
P30530|UFO_HUMAN
106
111
GqyqCL


 


481
P30532|ACHA5_HUMAN
279
284
GekiCL


 


482
P30566|PUR8_HUMAN
169
174
GkrcCL


 


483
P31323|KAP3_HUMAN
368
373
GtvkCL


 


484
P32004|L1CAM_HUMAN
308
313
GeyrCL


 


485
P32004|L1CAM_HUMAN
493
498
GryfCL


 


486
P32314|FOXN2_HUMAN
319
324
GirtCL


 


487
P32418|NAC1_HUMAN
414
419
GtyqCL


 


488
P32929|CGL_HUMAN
80
85
GakyCL


 


489
P32970|TNFL7_HUMAN
29
34
GlviCL


 


490
P33402|GCYA2_HUMAN
284
289
GncsCL


 


491
P34913|HYES_HUMAN
258
263
GpavCL


 


492
P34981|TRFR_HUMAN
94
99
GyvgCL


 


493
P34998|CRFR1_HUMAN
83
88
GyreCL


 


494
P35227|PCGF2_HUMAN
316
321
GslnCL


 


495
P35251|RFC1_HUMAN
402
407
GaenCL


 


496
P35270|SPRE_HUMAN
6
11
GravCL


 


497
P35367|HRH1_HUMAN
96
101
GrplCL


 


498
P35452|HXD12_HUMAN
176
181
GvasCL


 


499
P35498|SCN1A_HUMAN
964
969
GqamCL


 


500
P35499|SCN4A_HUMAN
774
779
GqamCL


 


501
P35503|UD13_HUMAN
514
519
GyrkCL


 


502
P35504|UD15_HUMAN
514
519
GyrkCL


 


503
P35555|FBN1_HUMAN
1259
1264
GeyrCL


 


504
P35555|FBN1_HUMAN
1385
1390
GsyrCL


 


505
P35555|FBN1_HUMAN
1416
1421
GngqCL


 


506
P35555|FBN1_HUMAN
1870
1875
GsfyCL


 


507
P35555|FBN1_HUMAN
2034
2039
GsfkCL


 


508
P35556|FBN2_HUMAN
1303
1308
GeyrCL


 


509
P35556|FBN2_HUMAN
1952
1957
GsynCL


 


510
P35556|FBN2_HUMAN
1994
1999
GsfkCL


 


511
P35556|FBN2_HUMAN
2076
2081
GgfqCL


 


512
P35590|TIE1_HUMAN
280
285
GltfCL


 


513
P35916|VGFR3_HUMAN
4
9
GaalCL


 


514
P35968|VGFR2_HUMAN
638
643
GdyvCL


 


515
P36509|UD12_HUMAN
510
515
GyrkCL


 


516
P36888|FLT3_HUMAN
99
104
GnisCL


 


517
P37058|DHB3_HUMAN
13
18
GllvCL


 


518
P38398|BRCA1_HUMAN
949
954
GsrfCL


 


519
P38571|LICH_HUMAN
7
12
GlvvCL


 


520
P38571|LICH_HUMAN
58
63
GyilCL


 


521
P38606|VATA1_HUMAN
390
395
GrvkCL


 


522
P38607|VATA2_HUMAN
388
393
GrvkCL


 


523
P39059|COFA1_HUMAN
8
13
GqcwCL


 


524
P40205|NCYM_HUMAN
100
105
GrppCL


 


525
P40939|ECHA_HUMAN
709
714
GfppCL


 


526
P41217|OX2G_HUMAN
117
122
GcymCL


 


527
P42331|RHG25_HUMAN
4
9
GqsaCL


 


528
P42345|FRAP_HUMAN
1479
1484
GrmrCL


 


529
P42785|PCP_HUMAN
339
344
GqvkCL


 


530
P42830|SCYB5_HUMAN
87
92
GkeiCL


 


531
P42892|ECE1_HUMAN
79
84
GlvaCL


 


532
P43378|PTN9_HUMAN
334
339
GdvpCL


 


533
P43403|ZAP70_HUMAN
113
118
GvfdCL


 


534
P43403|ZAP70_HUMAN
245
250
GliyCL


 


535
P46379|BAT3_HUMAN
872
877
GlfeCL


 


536
P46531|NOTC1_HUMAN
1354
1359
GslrCL


 


537
P47775|GPR12_HUMAN
166
171
GtsiCL


 


538
P47804|RGR_HUMAN
275
280
GiwqCL


 


539
P48048|IRK1_HUMAN
204
209
GgklCL


 


540
P48052|CBPA2_HUMAN
12
17
GhiyCL


 


541
P48059|PINC_HUMAN
176
181
GelyCL


 


542
P48067|SC6A9_HUMAN
457
462
GtqfCL


 


543
P48230|T4S4_HUMAN
5
10
GcarCL


 


544
P48745|NOV_HUMAN
60
65
GcscCL


 


545
P49247|RPIA_HUMAN
100
105
GgggCL


 


546
P49327|FAS_HUMAN
1455
1460
GlvnCL


 


547
P49588|SYAC_HUMAN
897
902
GkitCL


 


548
P49640|EVX1_HUMAN
345
350
GpcsCL


 


549
P49641|MA2A2_HUMAN
862
867
GwrgCL


 


550
P49646|YYY1_HUMAN
393
398
GetpCL


 


551
P49753|ACOT2_HUMAN
296
301
GgelCL


 


552
P49903|SPS1_HUMAN
323
328
GlliCL


 


553
P49910|ZN165_HUMAN
32
37
GqdtCL


 


554
P50851|LRBA_HUMAN
2736
2741
GpenCL


 


555
P51151|RAB9A_HUMAN
79
84
GsdcCL


 


556
P51168|SCNNB_HUMAN
532
537
GsvlCL


 


557
P51589|CP2J2_HUMAN
444
449
GkraCL


 


558
P51606|RENBP_HUMAN
37
42
GfftCL


 


559
P51674|GPM6A_HUMAN
170
175
GanlCL


 


560
P51685|CCR8_HUMAN
150
155
GttlCL


 


561
P51790|CLCN3_HUMAN
520
525
GaaaCL


 


562
P51790|CLCN3_HUMAN
723
728
GlrqCL


 


563
P51793|CLCN4_HUMAN
520
525
GaaaCL


 


564
P51793|CLCN4_HUMAN
721
726
GlrqCL


 


565
P51795|CLCN5_HUMAN
506
511
GaaaCL


 


566
P51795|CLCN5_HUMAN
707
712
GlrqCL


 


567
P51800|CLCKA_HUMAN
613
618
GhqqCL


 


568
P51801|CLCKB_HUMAN
613
618
GhqqCL


 


569
P51957|NEK4_HUMAN
322
327
GegkCL


 


570
P52306|GDS1_HUMAN
25
30
GcldCL


 


571
P52306|GDS1_HUMAN
265
270
GlveCL


 


572
P52429|DGKE_HUMAN
411
416
GtkdCL


 


573
P52744|ZN138_HUMAN
48
53
GlnqCL


 


574
P52789|HXK2_HUMAN
713
718
GdngCL


 


575
P52803|EFNA5_HUMAN
147
152
GrrsCL


 


576
P52823|STC1_HUMAN
55
60
GafaCL


 


577
P52848|NDST1_HUMAN
824
829
GktkCL


 


578
P52849|NDST2_HUMAN
302
307
GkrlCL


 


579
P52849|NDST2_HUMAN
823
828
GktrCL


 


580
P52961|NAR1_HUMAN
220
225
GiwtCL


 


581
P53355|DAPK1_HUMAN
1326
1331
GkdwCL


 


582
P54132|BLM_HUMAN
891
896
GiiyCL


 


583
P54277|PMS1_HUMAN
837
842
GmanCL


 


584
P54750|PDE1A_HUMAN
32
37
GilrCL


 


585
P54753|EPHB3_HUMAN
297
302
GegpCL


 


586
P54826|GAS1_HUMAN
19
24
GawlCL


 


587
P55160|NCKPL_HUMAN
938
943
GpieCL


 


588
P55268|LAMB2_HUMAN
501
506
GcdrCL


 


589
P55268|LAMB2_HUMAN
1063
1068
GqcpCL


 


590
P56192|SYMC_HUMAN
8
13
GvpgCL


 


591
P56749|CLD12_HUMAN
63
68
GssdCL


 


592
P57077|TAK1L_HUMAN
68
73
GflkCL


 


593
P57679|EVC_HUMAN
683
688
GssqCL


 


594
P58215|LOXL3_HUMAN
13
18
GlllCL


 


595
P58397|ATS12_HUMAN
447
452
GwgfCL


 


596
P58418|USH3A_HUMAN
69
74
GscgCL


 


597
P58512|CU067_HUMAN
166
171
GfpaCL


 


598
P59047|NALP5_HUMAN
64
69
GlqwCL


 


599
P59510|ATS20_HUMAN
458
463
GygeCL


 


600
P60370|KR105_HUMAN
32
37
GtapCL


 


601
P60371|KR106_HUMAN
16
21
GsrvCL


 


602
P60409|KR107_HUMAN
16
21
GsrvCL


 


603
P60413|KR10C_HUMAN
11
16
GsrvCL


 


604
P60602|CT052_HUMAN
38
43
GtfsCL


 


605
P61011|SRP54_HUMAN
129
134
GwktCL


 


606
P61550|ENT1_HUMAN
343
348
GnasCL


 


607
P61619|S61A1_HUMAN
143
148
GagiCL


 


608
P62072|TIM10_HUMAN
46
51
GesvCL


 


609
P62312|LSM6_HUMAN
32
37
GvlaCL


 


610
P62714|PP2AB_HUMAN
161
166
GqifCL


 


611
P67775|PP2AA_HUMAN
161
166
GqifCL


 


612
P68371|TBB2C_HUMAN
235
240
GvttCL


 


613
P69849|NOMO3_HUMAN
507
512
GkvsCL


 


614
P78310|CXAR_HUMAN
219
224
GsdqCL


 


615
P78324|SHPS1_HUMAN
12
17
GpllCL


 


616
P78325|ADAM8_HUMAN
101
106
GqdhCL


 


617
P78346|RPP30_HUMAN
253
258
GdedCL


 


618
P78357|CNTP1_HUMAN
1205
1210
GfsgCL


 


619
P78423|X3CL1_HUMAN
350
355
GllfCL


 


620
P78504|JAG1_HUMAN
898
903
GprpCL


 


621
P78509|RELN_HUMAN
2862
2867
GhgdCL


 


622
P78524|ST5_HUMAN
127
132
GvaaCL


 


623
P78549|NTHL1_HUMAN
286
291
GqqtCL


 


624
P78559|MAP1A_HUMAN
2433
2438
GpqgCX


 


625
P80162|SCYB6_HUMAN
87
92
GkqvCL


 


626
P82279|CRUM1_HUMAN
1092
1097
GlqgCL


 


627
P83105|HTRA4_HUMAN
10
15
GlgrCL


 


628
P98088|MUC5A_HUMAN
853
858
GcprCL


 


629
P98095|FBLN2_HUMAN
1047
1052
GsfrCL


 


630
P98153|IDD_HUMAN
289
294
GddpCL


 


631
P98160|PGBM_HUMAN
3181
3186
GtyvCL


 


632
P98161|PKD1_HUMAN
649
654
GaniCL


 


633
P98164|LRP2_HUMAN
1252
1257
GhpdCL


 


634
P98164|LRP2_HUMAN
3819
3824
GsadCL


 


635
P98173|FAM3A_HUMAN
83
88
GpkiCL


 


636
P98194|AT2C1_HUMAN
158
163
GdtvCL


 


637
Q00872|MYPC1_HUMAN
447
452
GkeiCL


 


638
Q00973|B4GN1_HUMAN
408
413
GlgnCL


 


639
Q01064|PDE1B_HUMAN
243
248
GmvhCL


 


640
Q01433|AMPD2_HUMAN
103
108
GpapCL


 


641
Q02246|CNTN2_HUMAN
107
112
GvyqCL


 


642
Q02246|CNTN2_HUMAN
203
208
GnysCL


 


643
Q02318|CP27A_HUMAN
472
477
GvraCL


 


644
Q02985|FHR3_HUMAN
188
193
GsitCL


 


645
Q03923|ZNF85_HUMAN
133
138
GlnqCL


 


646
Q03923|ZNF85_HUMAN
184
189
GmisCL


 


647
Q03924|ZN117_HUMAN
103
108
GlnqCL


 


648
Q03936|ZNF92_HUMAN
132
137
GlnqCL


 


649
Q03938|ZNF90_HUMAN
132
137
GlnqCL


 


650
Q04721|NOTC2_HUMAN
476
481
GgftCL


 


651
Q05469|LIPS_HUMAN
716
721
GeriCL


 


652
Q06730|ZN33A_HUMAN
530
535
GktfCL


 


653
Q06732|ZN11B_HUMAN
531
536
GktfCL


 


654
Q07325|SCYB9_HUMAN
70
75
GvqtCL


 


655
Q07617|SPAG1_HUMAN
133
138
GsnsCL


 


656
Q07954|LRP1_HUMAN
875
880
GdndCL


 


657
Q07954|LRP1_HUMAN
3001
3006
GsykCL


 


658
Q08629|TICN1_HUMAN
178
183
GpcpCL


 


659
Q09428|ABCC8_HUMAN
1073
1078
GivlCL


 


660
Q10471|GALT2_HUMAN
535
540
GsnlCL


 


661
Q12796|PNRC1_HUMAN
63
68
GdgpCL


 


662
Q12805|FBLN3_HUMAN
66
71
GgylCL


 


663
Q12809|KCNH2_HUMAN
719
724
GfpeCL


 


664
Q12841|FSTL1_HUMAN
48
53
GeptCL


 


665
Q12852|M3K12_HUMAN
90
95
GlfgCL


 


666
Q12860|CNTN1_HUMAN
110
115
GiyyCL


 


667
Q12882|DPYD_HUMAN
988
993
GctlCL


 


668
Q12933|TRAF2_HUMAN
387
392
GykmCL


 


669
Q12986|NFX1_HUMAN
537
542
GdfsCL


 


670
Q13077|TRAF1_HUMAN
302
307
GyklCL


 


671
Q13129|RLF_HUMAN
48
53
GlrpCL


 


672
Q13200|PSMD2_HUMAN
135
140
GereCL


 


673
Q13224|NMDE2_HUMAN
584
589
GynrCL


 


674
Q13224|NMDE2_HUMAN
1392
1397
GddqCL


 


675
Q13255|MGR1_HUMAN
136
141
GinrCL


 


676
Q13275|SEM3F_HUMAN
305
310
GghcCL


 


677
Q13308|PTK7_HUMAN
429
434
GyldCL


 


678
Q13309|SKP2_HUMAN
107
112
GifsCL


 


679
Q13322|GRB10_HUMAN
219
224
GlerCL


 


680
Q13370|PDE3B_HUMAN
253
258
GgagCL


 


681
Q13371|PHLP_HUMAN
200
205
GcmiCL


 


682
Q13387|JIP2_HUMAN
594
599
GlfsCL


 


683
Q13410|BT1A1_HUMAN
8
13
GlprCL


 


684
Q13444|ADA15_HUMAN
405
410
GmgsCL


 


685
Q13470|TNK1_HUMAN
105
110
GglkCL


 


686
Q13485|SMAD4_HUMAN
359
364
GdrfCL


 


687
Q13554|KCC2B_HUMAN
472
477
GpppCL


 


688
Q13591|SEM5A_HUMAN
819
824
GgmpCL


 


689
Q13591|SEM5A_HUMAN
876
881
GgdiCL


 


690
Q13639|5HT4R_HUMAN
89
94
GevfCL


 


691
Q13642|FHL1_HUMAN
23
28
GhhcCL


 


692
Q13686|ALKB1_HUMAN
300
305
GlphCL


 


693
Q13698|CAC1S_HUMAN
1210
1215
GglyCL


 


694
Q13751|LAMB3_HUMAN
449
454
GrclCL


 


695
Q13772|NCOA4_HUMAN
97
102
GqfnCL


 


696
Q13772|NCOA4_HUMAN
364
369
GnlkCL


 


697
Q13795|ARFRP_HUMAN
159
164
GrrdCL


 


698
Q13822|ENPP2_HUMAN
21
26
GvniCL


 


699
Q13885|TBB2A_HUMAN
235
240
GvttCL


 


700
Q14008|CKAP5_HUMAN
109
114
GieiCL


 


701
Q14008|CKAP5_HUMAN
1237
1242
GvigCL


 


702
Q14114|LRP8_HUMAN
175
180
GnrsCL


 


703
Q14114|LRP8_HUMAN
336
341
GlneCL


 


704
Q14159|K0146_HUMAN
513
518
GtraCL


 


705
Q14264|ENR1_HUMAN
358
363
GeltCL


 


706
Q14315|FLNC_HUMAN
1649
1654
GlgaCL


 


707
Q14344|GNA13_HUMAN
314
319
GdphCL


 


708
Q14392|LRC32_HUMAN
360
365
GslpCL


 


709
Q14393|GAS6_HUMAN
138
143
GnffCL


 


710
Q14393|GAS6_HUMAN
217
222
GsysCL


 


711
Q14435|GALT3_HUMAN
93
98
GerpCL


 


712
Q14435|GALT3_HUMAN
513
518
GqplCL


 


713
Q14451|GRB7_HUMAN
517
522
GilpCL


 


714
Q14520|HABP2_HUMAN
121
126
GrgqCL


 


715
Q14524|SCN5A_HUMAN
911
916
GqslCL


 


716
Q14566|MCM6_HUMAN
154
159
GtflCL


 


717
Q14593|ZN273_HUMAN
100
105
GlnqCL


 


718
Q14656|ITBA1_HUMAN
197
202
GvlsCL


 


719
Q14669|TRIPC_HUMAN
562
567
GladCL


 


720
Q14669|TRIPC_HUMAN
1136
1141
GgaeCL


 


721
Q14703|MBTP1_HUMAN
845
850
GdsnCL


 


722
Q14714|SSPN_HUMAN
91
96
GiivCL


 


723
Q14766|LTB1L_HUMAN
1139
1144
GsfrCL


 


724
Q14766|LTB1L_HUMAN
1560
1565
GsykCL


 


725
Q14767|LTBP2_HUMAN
990
995
GsytCL


 


726
Q14767|LTBP2_HUMAN
1156
1161
GsyqCL


 


727
Q14767|LTBP2_HUMAN
1197
1202
GsffCL


 


728
Q14767|LTBP2_HUMAN
1238
1243
GsfnCL


 


729
Q14767|LTBP2_HUMAN
1324
1329
GsfrCL


 


730
Q14767|LTBP2_HUMAN
1366
1371
GsflCL


 


731
Q14774|HLX1_HUMAN
483
488
GalgCL


 


732
Q14916|NPT1_HUMAN
110
115
GfalCL


 


733
Q14916|NPT1_HUMAN
207
212
GcavCL


 


734
Q14940|SL9A5_HUMAN
576
581
GsgaCL


 


735
Q14957|NMDE3_HUMAN
941
946
GpspCL


 


736
Q15021|CND1_HUMAN
730
735
GtiqCL


 


737
Q15034|HERC3_HUMAN
145
150
GnwhCL


 


738
Q15048|LRC14_HUMAN
281
286
GrftCL


 


739
Q15058|KIF14_HUMAN
438
443
GfntCL


 


740
Q15061|WDR43_HUMAN
103
108
GtctCL


 


741
Q15147|PLCB4_HUMAN
987
992
GgsnCL


 


742
Q15155|NOMO1_HUMAN
507
512
GkvsCL


 


743
Q15274|NADC_HUMAN
92
97
GpahCL


 


744
Q15303|ERBB4_HUMAN
516
521
GpdqCL


 


745
Q15334|L2GL1_HUMAN
722
727
GvvrCL


 


746
Q15399|TLR1_HUMAN
663
668
GmqiCL


 


747
Q15413|RYR3_HUMAN
229
234
GhdeCL


 


748
Q15413|RYR3_HUMAN
1656
1661
GlrtCL


 


749
Q15418|KS6A1_HUMAN
548
553
GnpeCL


 


750
Q15546|PAQRB_HUMAN
185
190
GliyCL


 


751
Q15633|TRBP2_HUMAN
321
326
GlcqCL


 


752
Q15650|TRIP4_HUMAN
196
201
GsgpCL


 


753
Q15652|JHD2C_HUMAN
1864
1869
GfvvCL


 


754
Q15735|PI5PA_HUMAN
379
384
GpgrCL


 


755
Q15746|MYLK_HUMAN
229
234
GvytCL


 


756
Q15746|MYLK_HUMAN
579
584
GtytCL


 


757
Q15858|SCN9A_HUMAN
940
945
GqamCL


 


758
Q15911|ATBF1_HUMAN
3527
3532
GsyhCL


 


759
Q16342|PDCD2_HUMAN
121
126
GesvCL


 


760
Q16363|LAMA4_HUMAN
1001
1006
GfvgCL


 


761
Q16549|PCSK7_HUMAN
16
21
GlptCL


 


762
Q16617|NKG7_HUMAN
15
20
GlmfCL


 


763
Q16647|PTGIS_HUMAN
437
442
GhnhCL


 


764
Q16787|LAMA3_HUMAN
1526
1531
GvssCL


 


765
Q30KQ9|DB111_HUMAN
60
65
GthcCL


 


766
Q32MQ0|ZN750_HUMAN
121
126
GthrCL


 


767
Q3KNT7|NSN5B_HUMAN
134
139
GaehCL


 


768
Q3LI83|KR241_HUMAN
153
158
GqlnCL


 


769
Q3SYG4|PTHB1_HUMAN
822
827
GgrlCL


 


770
Q3T8J9|GON4L_HUMAN
1740
1745
GcadCL


 


771
Q495M9|USH1G_HUMAN
76
81
GhlhCL


 


772
Q496M8|CI094_HUMAN
170
175
GefsCL


 


773
Q499Z4|ZN672_HUMAN
40
45
GrfrCL


 


774
Q4G0F5|VP26B_HUMAN
167
172
GiedCL


 


775
Q4KMG0|CDON_HUMAN
93
98
GyyqCL


 


776
Q53G59|KLH12_HUMAN
426
431
GviyCL


 


777
Q53H47|SETMR_HUMAN
72
77
GtcsCL


 


778
Q53R12|T4S20_HUMAN
213
218
GflgCL


 


779
Q58EX2|SDK2_HUMAN
469
474
GtytCL


 


780
Q5HYK3|COQ5_HUMAN
240
245
GrflCL


 


781
Q5IJ48|CRUM2_HUMAN
243
248
GsfrCL


 


782
Q5JPE7|NOMO2_HUMAN
507
512
GkvsCL


 


783
Q5JQC9|AKAP4_HUMAN
242
247
GkskCL


 


784
Q5JVG8|ZN506_HUMAN
132
137
GlkqCL


 


785
Q5JWF2|GNAS1_HUMAN
2
7
GvrnCL


 


786
Q5JWF2|GNAS1_HUMAN
584
589
GtsgCL


 


787
Q5JWF8|CT134_HUMAN
111
116
GccvCL


 


788
Q5MJ68|SPDYC_HUMAN
138
143
GkdwCL


 


789
Q5NUL3|GP120_HUMAN
72
77
GataCL


 


790
Q5SRN2|CF010_HUMAN
117
122
GsikCL


 


791
Q5T2D3|OTUD3_HUMAN
72
77
GdgnCL


 


792
Q5T5C0|STXB5_HUMAN
322
327
GrrpCL


 


793
Q5T751|LCE1C_HUMAN
72
77
GggcCL


 


794
Q5T752|LCE1D_HUMAN
68
73
GggcCL


 


795
Q5T753|LCE1E_HUMAN
72
77
GggcCL


 


796
Q5T754|LCE1F_HUMAN
72
77
GggcCL


 


797
Q5T7P2|LCE1A_HUMAN
64
69
GggcCL


 


798
Q5T7P3|LCE1B_HUMAN
72
77
GggcCL


 


799
Q5TA78|LCE4A_HUMAN
55
60
GggcCL


 


800
Q5TA79|LCE2A_HUMAN
64
69
GggcCL


 


801
Q5TA82|LCE2D_HUMAN
68
73
GggcCL


 


802
Q5TCM9|LCE5A_HUMAN
64
69
GggcCL


 


803
Q5TEA3|CT194_HUMAN
465
470
GgngCL


 


804
Q5TEJ8|ICB1_HUMAN
39
44
GnecCL


 


805
Q5THJ4|VP13D_HUMAN
1215
1220
GslgCL


 


806
Q5VST9|OBSCN_HUMAN
3315
3320
GdryCL


 


807
Q5VST9|OBSCN_HUMAN
4189
4194
GvqwCL


 


808
Q5VST9|OBSCN_HUMAN
5195
5200
GvyrCL


 


809
Q5VST9|OBSCN_HUMAN
6425
6430
GvytCL


 


810
Q5VT25|MRCKA_HUMAN
1325
1330
GaltCL


 


811
Q5VUA4|ZN318_HUMAN
1984
1989
GpspCL


 


812
Q5VZ18|SHE_HUMAN
8
13
GasaCL


 


813
Q5VZM2|RRAGB_HUMAN
366
371
GpkqCL


 


814
Q5W111|CLLD6_HUMAN
50
55
GtggCL


 


815
Q5XUX1|FBXW9_HUMAN
184
189
GgslCL


 


816
Q5ZPR3|CD276_HUMAN
216
221
GtysCL


 


817
Q5ZPR3|CD276_HUMAN
434
439
GtysCL


 


818
Q5ZPR3|CD276_HUMAN
472
477
GlsvCL


 


819
Q63ZY6|NSN5C_HUMAN
216
221
GaehCL


 


820
Q63ZY6|NSN5C_HUMAN
293
298
GkgrCL


 


821
Q68CP9|ARID2_HUMAN
566
571
GfykCL


 


822
Q6BDS2|URFB1_HUMAN
549
554
GnlfCL


 


823
Q6GQQ9|OTU7B_HUMAN
190
195
GdgnCL


 


824
Q6GTX8|LAIR1_HUMAN
10
15
GlvlCL


 


825
Q6IS24|GLTL3_HUMAN
564
569
GtgrCL


 


826
Q6ISS4|LAIR2_HUMAN
10
15
GlvlCL


 


827
Q6ISS4|LAIR2_HUMAN
97
102
GlyrCL


 


828
Q6N022|TEN4_HUMAN
139
144
GrssCL


 


829
Q6NUM9|RETST_HUMAN
366
371
GnarCL


 


830
Q6P1M0|S27A4_HUMAN
297
302
GigqCL


 


831
Q6P1R4|DUS1L_HUMAN
209
214
GniqCL


 


832
Q6P587|FAHD1_HUMAN
96
101
GyalCL


 


833
Q6P656|CO026_HUMAN
144
149
GqdfCL


 


834
Q6PCB7|S27A1_HUMAN
300
305
GvgqCL


 


835
Q6PCT2|FXL19_HUMAN
222
227
GgdaCL


 


836
Q6Q0C0|TRAF7_HUMAN
397
402
GpvwCL


 


837
Q6Q4G3|LAEVR_HUMAN
794
799
GledCL


 


838
Q6TGC4|PADI6_HUMAN
22
27
GteiCL


 


839
Q6UB99|ANR11_HUMAN
498
503
GssgCL


 


840
Q6UWJ8|C16L2_HUMAN
15
20
GgccCL


 


841
Q6UWN5|LYPD5_HUMAN
15
20
GaalCL


 


842
Q6UX01|LMBRL_HUMAN
394
399
GncvCL


 


843
Q6UX53|MET7B_HUMAN
199
204
GdgcCL


 


844
Q6UX65|TMM77_HUMAN
99
104
GilsCL


 


845
Q6UXV0|GFRAL_HUMAN
127
132
GmwsCL


 


846
Q6UY09|CEA20_HUMAN
226
231
GlyrCL


 


847
Q6V0L0|CP26C_HUMAN
455
460
GarsCL


 


848
Q6V0L0|CP26C_HUMAN
517
522
GnglCL


 


849
Q6VVB1|NHLC1_HUMAN
47
52
GhvvCL


 


850
Q6VVX0|CP2R1_HUMAN
444
449
GrrhCL


 


851
Q6W4X9|MUC6_HUMAN
1095
1100
GdceCL


 


852
Q6WN34|CRDL2_HUMAN
54
59
GlmyCL


 


853
Q6ZN16|M3K15_HUMAN
82
87
GarqCL


 


854
Q6ZN17|LN28B_HUMAN
103
108
GgspCL


 


855
Q6ZRI6|CO039_HUMAN
141
146
GlstCL


 


856
Q6ZRQ5|CF167_HUMAN
1116
1121
GilkCL


 


857
Q6ZSY5|PPR3F_HUMAN
647
652
GaevCL


 


858
Q6ZV89|SH2D5_HUMAN
195
200
GghsCL


 


859
Q6ZVD8|PHLPL_HUMAN
5
10
GsrnCL


 


860
Q6ZW76|ANKS3_HUMAN
632
637
GqalCL


 


861
Q75N90|FBN3_HUMAN
551
556
GsfsCL


 


862
Q75N90|FBN3_HUMAN
1217
1222
GghrCL


 


863
Q75N90|FBN3_HUMAN
1826
1831
GsymCL


 


864
Q75N90|FBN3_HUMAN
1866
1871
GsynCL


 


865
Q75N90|FBN3_HUMAN
1908
1913
GsfhCL


 


866
Q75N90|FBN3_HUMAN
1990
1995
GsfqCL


 


867
Q7L099|RUFY3_HUMAN
37
42
GewlCL


 


868
Q7L0J3|SV2A_HUMAN
230
235
GrrqCL


 


869
Q7L3T8|SYPM_HUMAN
149
154
GkeyCL


 


870
Q7L622|K1333_HUMAN
310
315
GitdCL


 


871
Q7LBC6|JHD2B_HUMAN
1049
1054
GfgvCL


 


872
Q7LBC6|JHD2B_HUMAN
1388
1393
GrllCL


 


873
Q7RTN6|STRAD_HUMAN
294
299
GtvpCL


 


874
Q7RTP0|NIPA1_HUMAN
122
127
GklgCL


 


875
Q7RTU9|STRC_HUMAN
1077
1082
GacsCL


 


876
Q7RTX0|TS1R3_HUMAN
20
25
GaplCL


 


877
Q7Z2W7|TRPM8_HUMAN
652
657
GgsnCL


 


878
Q7Z333|SETX_HUMAN
1106
1111
GekkCL


 


879
Q7Z3K3|POGZ_HUMAN
749
754
GrqtCL


 


880
Q7Z3T1|OR2W3_HUMAN
108
113
GgveCL


 


881
Q7Z401|MYCPP_HUMAN
948
953
GsadCL


 


882
Q7Z460|CLAP1_HUMAN
146
151
GiclCL


 


883
Q7Z4S6|KI21A_HUMAN
1493
1498
GpvmCL


 


884
Q7Z5G4|GOGA7_HUMAN
68
73
GclaCL


 


885
Q7Z5K2|WAPL_HUMAN
850
855
GaerCL


 


886
Q7Z713|ANR37_HUMAN
75
80
GsleCL


 


887
Q7Z7E8|UB2Q1_HUMAN
36
41
GpgpCL


 


888
Q7Z7M0|MEGF8_HUMAN
403
408
GcgwCL


 


889
Q7Z7M1|GP144_HUMAN
343
348
GselCL


 


890
Q86SG6|NEK8_HUMAN
418
423
GsngCL


 


891
Q86SQ6|GP123_HUMAN
1058
1063
GraaCL


 


892
Q86SQ6|GP123_HUMAN
1091
1096
GhasCL


 


893
Q86T20|CF001_HUMAN
75
80
GvldCL


 


894
Q86T65|DAAM2_HUMAN
570
575
GappCL


 


895
Q86TX2|ACOT1_HUMAN
234
239
GgelCL


 


896
Q86U44|MTA70_HUMAN
479
484
GkehCL


 


897
Q86UE6|LRTM1_HUMAN
19
24
GvvlCL


 


898
Q86UK0|ABCAC_HUMAN
1251
1256
GwlcCL


 


899
Q86UK5|LBN_HUMAN
26
31
GgrgCL


 


900
Q86UQ4|ABCAD_HUMAN
4056
4061
GppfCL


 


901
Q86UQ4|ABCAD_HUMAN
4932
4937
GsfkCL


 


902
Q86UU1|PHLB1_HUMAN
119
124
GcmlCL


 


903
Q86UU1|PHLB1_HUMAN
1245
1250
GvdtCL


 


904
Q86UV5|UBP48_HUMAN
50
55
GnpnCL


 


905
Q86UW9|DTX2_HUMAN
347
352
GlpvCL


 


906
Q86V24|ADR2_HUMAN
190
195
GailCL


 


907
Q86V71|ZN429_HUMAN
132
137
GlnqCL


 


908
Q86VH4|LRTM4_HUMAN
271
276
GtfkCL


 


909
Q86WB7|UN93A_HUMAN
178
183
GasdCL


 


910
Q86WG5|MTMRD_HUMAN
369
374
GyrsCL


 


911
Q86WK7|AMGO3_HUMAN
348
353
GlfvCL


 


912
Q86WR7|CJ047_HUMAN
84
89
GgvcCL


 


913
Q86X76|NIT1_HUMAN
288
293
GpglCL


 


914
Q86XN8|RKHD1_HUMAN
192
197
GtdvCL


 


915
Q86Y01|DTX1_HUMAN
345
350
GlpvCL


 


916
Q86Y56|HEAT2_HUMAN
271
276
GwllCL


 


917
Q86YC3|LRC33_HUMAN
396
401
GlasCL


 


918
Q8IU80|TMPS6_HUMAN
503
508
GqpdCL


 


919
Q8IUK8|CBLN2_HUMAN
27
32
GcgsCL


 


920
Q8IUL8|CILP2_HUMAN
464
469
GcqkCL


 


921
Q8IVF6|ANR18_HUMAN
706
711
GykkCL


 


922
Q8IVH4|MMAA_HUMAN
96
101
GqraCL


 


923
Q8IWB7|WDFY1_HUMAN
200
205
GsvaCL


 


924
Q8IWN6|CX052_HUMAN
89
94
GskrCL


 


925
Q8IWV2|CNTN4_HUMAN
380
385
GmyqCL


 


926
Q8IWY4|SCUB1_HUMAN
342
347
GsfqCL


 


927
Q8IX30|SCUB3_HUMAN
337
342
GsfqCL


 


928
Q8IXI1|MIRO2_HUMAN
515
520
GqtpCL


 


929
Q8IXW0|CK035_HUMAN
268
273
GslpCL


 


930
Q8IY26|PPAC2_HUMAN
149
154
GtlyCL


 


931
Q8IY49|PAQRA_HUMAN
216
221
GvfyCL


 


932
Q8IYB9|ZN595_HUMAN
132
137
GvyqCL


 


933
Q8IYG6|LRC56_HUMAN
194
199
GnlvCL


 


934
Q8IZ96|CKLF1_HUMAN
112
117
GgslCL


 


935
Q8IZD0|SAM14_HUMAN
95
100
GgsfCL


 


936
Q8IZE3|PACE1_HUMAN
322
327
GetpCL


 


937
Q8IZF4|GP114_HUMAN
521
526
GkllCL


 


938
Q8IZJ1|UNC5B_HUMAN
547
552
GtfgCL


 


939
Q8IZL8|PELP1_HUMAN
317
322
GlarCL


 


940
Q8IZY2|ABCA7_HUMAN
2001
2006
GrfrCL


 


941
Q8N122|RPTOR_HUMAN
549
554
GqeaCL


 


942
Q8N122|RPTOR_HUMAN
1302
1307
GaisCL


 


943
Q8N1F7|NUP93_HUMAN
518
523
GdppCL


 


944
Q8N1G0|ZN687_HUMAN
1133
1138
GaqqCL


 


945
Q8N283|ANR35_HUMAN
65
70
GlteCL


 


946
Q8N283|ANR35_HUMAN
703
708
GlwdCL


 


947
Q8N357|CB018_HUMAN
57
62
GefsCL


 


948
Q8N3C7|RSNL2_HUMAN
201
206
GavkCL


 


949
Q8N3V7|SYNPO_HUMAN
28
33
GsyrCL


 


950
Q8N441|FGRL1_HUMAN
334
339
GmyiCL


 


951
Q8N442|GUF1_HUMAN
334
339
GdtlCL


 


952
Q8N4B4|FBX39_HUMAN
114
119
GllsCL


 


953
Q8N5D0|WDTC1_HUMAN
48
53
GcvnCL


 


954
Q8N5D6|GBGT1_HUMAN
9
14
GlgfCL


 


955
Q8N655|CJ012_HUMAN
468
473
GdvkCL


 


956
Q8N6F8|WBS27_HUMAN
160
165
GglvCL


 


957
Q8N6T3|ARFG1_HUMAN
38
43
GiwiCL


 


958
Q8N6V9|TEX9_HUMAN
3
8
GrslCL


 


959
Q8N6Y1|PCD20_HUMAN
27
32
GpfsCL


 


960
Q8N6Y1|PCD20_HUMAN
881
886
GiyiCL


 


961
Q8N726|CD2A2_HUMAN
160
165
GrarCL


 


962
Q8N813|CC056_HUMAN
42
47
GsctCL


 


963
Q8N895|ZN366_HUMAN
695
700
GrdeCL


 


964
Q8N8A2|ANR44_HUMAN
543
548
GhrqCL


 


965
Q8N8A2|ANR44_HUMAN
645
650
GhtlCL


 


966
Q8N8Q9|NIPA2_HUMAN
112
117
GkigCL


 


967
Q8N8R3|MCATL_HUMAN
133
138
GsldCL


 


968
Q8N9B4|ANR42_HUMAN
142
147
GrlgCL


 


969
Q8N9B4|ANR42_HUMAN
281
286
GhieCL


 


970
Q8N9L9|ACOT4_HUMAN
234
239
GadiCL


 


971
Q8NB46|ANR52_HUMAN
434
439
GnveCL


 


972
Q8NB46|ANR52_HUMAN
732
737
GcedCL


 


973
Q8NB46|ANR52_HUMAN
802
807
GhedCL


 


974
Q8NB49|AT11C_HUMAN
110
115
GyedCL


 


975
Q8NBJ9|SIDT2_HUMAN
296
301
GmlfCL


 


976
Q8NBV4|PPAC3_HUMAN
128
133
GtilCL


 


977
Q8NCL4|GALT6_HUMAN
505
510
GtnqCL


 


978
Q8NCL4|GALT6_HUMAN
593
598
GsgtCL


 


979
Q8NCN4|RN169_HUMAN
67
72
GcagCL


 


980
Q8NDX1|PSD4_HUMAN
183
188
GlkcCL


 


981
Q8NDX1|PSD4_HUMAN
821
826
GedhCL


 


982
Q8NEN9|PDZD8_HUMAN
724
729
GgliCL


 


983
Q8NFP4|MDGA1_HUMAN
622
627
GsaaCL


 


984
Q8NFP9|NBEA_HUMAN
2819
2824
GpenCL


 


985
Q8NFU7|CXXC6_HUMAN
1660
1665
GvtaCL


 


986
Q8NG94|O11H1_HUMAN
112
117
GtseCL


 


987
Q8NG99|OR7G2_HUMAN
109
114
GlenCL


 


988
Q8NGC9|O11H4_HUMAN
118
123
GtteCL


 


989
Q8NGH6|O52L2_HUMAN
96
101
GytvCL


 


990
Q8NGH7|O52L1_HUMAN
96
101
GyivCL


 


991
Q8NGI2|O52N4_HUMAN
95
100
GfdeCL


 


992
Q8NGJ0|OR5A1_HUMAN
111
116
GlseCL


 


993
Q8NGK5|O52M1_HUMAN
95
100
GldaCL


 


994
Q8NGR9|OR1N2_HUMAN
112
117
GldnCL


 


995
Q8NGS6|O13C3_HUMAN
108
113
GsteCL


 


996
Q8NGT2|O13J1_HUMAN
108
113
GsteCL


 


997
Q8NGT5|OR9A2_HUMAN
247
252
GygsCL


 


998
Q8NGT9|O2A42_HUMAN
107
112
GhseCL


 


999
Q8NGU2|OR9A4_HUMAN
251
256
GygsCL


 


1000
Q8NGZ9|O2T10_HUMAN
109
114
GaecCL


 


1001
Q8NH09|OR8S1_HUMAN
109
114
GteaCL


 


1002
Q8NH19|O10AG_HUMAN
99
104
GgteCL


 


1003
Q8NH40|OR6S1_HUMAN
66
71
GnlsCL


 


1004
Q8NHA8|OR1FC_HUMAN
50
55
GsdhCL


 


1005
Q8NHU2|CT026_HUMAN
158
163
GnipCL


 


1006
Q8NHU2|CT026_HUMAN
582
587
GfksCL


 


1007
Q8NHW6|OTOSP_HUMAN
8
13
GlalCL


 


1008
Q8NHX4|SPTA3_HUMAN
175
180
GsrsCL


 


1009
Q8NHY2|RFWD2_HUMAN
628
633
GkpyCL


 


1010
Q8NHY3|GA2L2_HUMAN
463
468
GpaeCL


 


1011
Q8TB24|RIN3_HUMAN
31
36
GmrlCL


 


1012
Q8TB24|RIN3_HUMAN
971
976
GsppCL


 


1013
Q8TCB7|METL6_HUMAN
89
94
GvgnCL


 


1014
Q8TCN5|ZN507_HUMAN
142
147
GmyrCL


 


1015
Q8TCT7|PSL1_HUMAN
262
267
GlysCL


 


1016
Q8TCT7|PSL1_HUMAN
329
334
GiafCL


 


1017
Q8TCT8|PSL2_HUMAN
321
326
GiafCL


 


1018
Q8TD26|CHD6_HUMAN
1627
1632
GnlcCL


 


1019
Q8TD43|TRPM4_HUMAN
238
243
GthgCL


 


1020
Q8TD43|TRPM4_HUMAN
306
311
GaadCL


 


1021
Q8TD43|TRPM4_HUMAN
650
655
GdatCL


 


1022
Q8TD43|TRPM4_HUMAN
764
769
GgrrCL


 


1023
Q8TDJ6|DMXL2_HUMAN
188
193
GkddCL


 


1024
Q8TDM6|DLG5_HUMAN
1672
1677
GvkdCL


 


1025
Q8TDN4|CABL1_HUMAN
135
140
GsgpCL


 


1026
Q8TDU6|GPBAR_HUMAN
81
86
GywsCL


 


1027
Q8TDU9|RL3R2_HUMAN
187
192
GvrlCL


 


1028
Q8TDV0|GP151_HUMAN
183
188
GvemCL


 


1029
Q8TDX9|PK1L1_HUMAN
317
322
GealCL


 


1030
Q8TDY2|RBCC1_HUMAN
897
902
GelvCL


 


1031
Q8TDZ2|MICA1_HUMAN
743
748
GhfyCL


 


1032
Q8TE49|OTU7A_HUMAN
206
211
GdgnCL


 


1033
Q8TE58|ATS15_HUMAN
418
423
GhgdCL


 


1034
Q8TE85|GRHL3_HUMAN
429
434
GvkgCL


 


1035
Q8TEM1|PO210_HUMAN
1489
1494
GdvlCL


 


1036
Q8TF62|AT8B4_HUMAN
282
287
GfliCL


 


1037
Q8TF76|HASP_HUMAN
190
195
GtsaCL


 


1038
Q8WTV0|SCRB1_HUMAN
319
324
GfcpCL


 


1039
Q8WUB8|PHF10_HUMAN
320
325
GhpsCL


 


1040
Q8WUM0|NU133_HUMAN
112
117
GgwaCL


 


1041
Q8WWQ8|STAB2_HUMAN
1358
1363
GngiCL


 


1042
Q8WWQ8|STAB2_HUMAN
2026
2031
GsgqCL


 


1043
Q8WWX0|ASB5_HUMAN
179
184
GhheCL


 


1044
Q8WWZ1|IL1FA_HUMAN
63
68
GgsrCL


 


1045
Q8WXI2|CNKR2_HUMAN
22
27
GlddCL


 


1046
Q8WXI7|MUC16_HUMAN
22110
22115
GlitCL


 


1047
Q8WXK4|ASB12_HUMAN
75
80
GhlsCL


 


1048
Q8WXS8|ATS14_HUMAN
489
494
GyqtCL


 


1049
Q8WXS8|ATS14_HUMAN
587
592
GgrpCL


 


1050
Q8WYB5|MYST4_HUMAN
244
249
GhpsCL


 


1051
Q8WYP5|AHTF1_HUMAN
112
117
GsvlCL


 


1052
Q8WYP5|AHTF1_HUMAN
318
323
GnrkCL


 


1053
Q8WYP5|AHTF1_HUMAN
526
531
GynrCL


 


1054
Q8WZ42|TITIN_HUMAN
4919
4924
GkytCL


 


1055
Q8WZ42|TITIN_HUMAN
5147
5152
GsavCL


 


1056
Q8WZ42|TITIN_HUMAN
7829
7834
GdysCL


 


1057
Q8WZ42|TITIN_HUMAN
16742
16747
GaqdCL


 


1058
Q8WZ42|TITIN_HUMAN
20237
20242
GtnvCL


 


1059
Q8WZ73|RFFL_HUMAN
81
86
GprlCL


 


1060
Q8WZ74|CTTB2_HUMAN
924
929
GfknCL


 


1061
Q92481|AP2B_HUMAN
379
384
GiqsCL


 


1062
Q92496|FHR4_HUMAN
130
135
GsitCL


 


1063
Q92520|FAM3C_HUMAN
82
87
GpkiCL


 


1064
Q92527|ANKR7_HUMAN
148
153
GeppCL


 


1065
Q92529|SHC3_HUMAN
581
586
GselCL


 


1066
Q92546|K0258_HUMAN
248
253
GtvaCL


 


1067
Q92583|CCL17_HUMAN
30
35
GrecCL


 


1068
Q92621|NU205_HUMAN
950
955
GfveCL


 


1069
Q92636|FAN_HUMAN
824
829
GtdgCL


 


1070
Q92673|SORL_HUMAN
1415
1420
GpstCL


 


1071
Q92750|TAF4B_HUMAN
410
415
GaaiCL


 


1072
Q92752|TENR_HUMAN
293
298
GqrqCL


 


1073
Q92782|DPF1_HUMAN
256
261
GhpsCL


 


1074
Q92783|STAM1_HUMAN
41
46
GpkdCL


 


1075
Q92785|REQU_HUMAN
302
307
GhpsCL


 


1076
Q92794|MYST3_HUMAN
237
242
GhpsCL


 


1077
Q92832|NELL1_HUMAN
618
623
GgfdCL


 


1078
Q92854|SEM4D_HUMAN
620
625
GvyqCL


 


1079
Q92900|RENT1_HUMAN
370
375
GdeiCL


 


1080
Q92932|PTPR2_HUMAN
35
40
GrlgCL


 


1081
Q92932|PTPR2_HUMAN
634
639
GliyCL


 


1082
Q92947|GCDH_HUMAN
285
290
GpfgCL


 


1083
Q92947|GCDH_HUMAN
346
351
GlhaCL


 


1084
Q92952|KCNN1_HUMAN
361
366
GkgvCL


 


1085
Q92956|TNR14_HUMAN
89
94
GlskCL


 


1086
Q92968|PEX13_HUMAN
216
221
GtvaCL


 


1087
Q93038|TNR25_HUMAN
66
71
GnstCL


 


1088
Q969L2|MAL2_HUMAN
37
42
GafvCL


 


1089
Q969P0|IGSF8_HUMAN
402
407
GtyrCL


 


1090
Q96A54|ADR1_HUMAN
179
184
GavlCL


 


1091
Q96AP0|ACD_HUMAN
269
274
GalvCL


 


1092
Q96AQ2|TM125_HUMAN
71
76
GtvlCL


 


1093
Q96B26|EXOS8_HUMAN
230
235
GklcCL


 


1094
Q96B86|RGMA_HUMAN
311
316
GlylCL


 


1095
Q96BD0|SO4A1_HUMAN
698
703
GletCL


 


1096
Q96CE8|T4S18_HUMAN
8
13
GclsCL


 


1097
Q96CW5|GCP3_HUMAN
190
195
GvgdCL


 


1098
Q96D59|RN183_HUMAN
95
100
GhqlCL


 


1099
Q96DN5|WDR67_HUMAN
52
57
GtgdCL


 


1100
Q96DZ5|CLR59_HUMAN
212
217
GaakCL


 


1101
Q96EP1|CHFR_HUMAN
528
533
GcygCL


 


1102
Q96EY5|F125A_HUMAN
51
56
GyflCL


 


1103
Q96EZ4|MYEOV_HUMAN
232
237
GrraCL


 


1104
Q96F46|I17RA_HUMAN
628
633
GsqaCL


 


1105
Q96GC6|ZN274_HUMAN
256
261
GttcCL


 


1106
Q96H40|ZN486_HUMAN
132
137
GlnqCL


 


1107
Q96H96|COQ2_HUMAN
172
177
GvllCL


 


1108
Q96I82|KAZD1_HUMAN
249
254
GtyrCL


 


1109
Q96IV0|NGLY1_HUMAN
70
75
GaveCL


 


1110
Q96IW7|SC22A_HUMAN
234
239
GtaaCL


 


1111
Q96J02|ITCH_HUMAN
160
165
GvslCL


 


1112
Q96J94|PIWL1_HUMAN
674
679
GlkvCL


 


1113
Q96JH7|VCIP1_HUMAN
215
220
GdghCL


 


1114
Q96JK2|WDR22_HUMAN
178
183
GepfCL


 


1115
Q96JT2|S45A3_HUMAN
27
32
GlevCL


 


1116
Q96JT2|S45A3_HUMAN
485
490
GrgiCL


 


1117
Q96K31|CH076_HUMAN
98
103
GqarCL


 


1118
Q96KC8|DNJC1_HUMAN
228
233
GiwfCL


 


1119
Q96KM6|K1196_HUMAN
782
787
GkyrCL


 


1120
Q96LC7|SIG10_HUMAN
373
378
GqslCL


 


1121
Q96LD4|TRI47_HUMAN
25
30
GhnfCL


 


1122
Q96LQ0|CN050_HUMAN
366
371
GeprCL


 


1123
Q96ME1|FXL18_HUMAN
352
357
GcvhCL


 


1124
Q96ME7|ZN512_HUMAN
320
325
GqpeCL


 


1125
Q96ME7|ZN512_HUMAN
438
443
GkykCL


 


1126
Q96MU7|YTDC1_HUMAN
485
490
GtqlCL


 


1127
Q96MU8|KREM1_HUMAN
53
58
GgkpCL


 


1128
Q96NL3|ZN599_HUMAN
373
378
GktfCL


 


1129
Q96NX9|DACH2_HUMAN
585
590
GnyyCL


 


1130
Q96P11|NSUN5_HUMAN
400
405
GaehCL


 


1131
Q96PH1|NOX5_HUMAN
272
277
GcgqCL


 


1132
Q96PL5|ERMAP_HUMAN
122
127
GsyrCL


 


1133
Q96PP9|GBP4_HUMAN
321
326
GavpCL


 


1134
Q96Q04|LMTK3_HUMAN
676
681
GacsCL


 


1135
Q96Q15|SMG1_HUMAN
2809
2814
GnvtCL


 


1136
Q96Q27|ASB2_HUMAN
101
106
GqvgCL


 


1137
Q96Q27|ASB2_HUMAN
135
140
GhldCL


 


1138
Q96Q91|B3A4_HUMAN
455
460
GaafCL


 


1139
Q96QG7|MTMR9_HUMAN
85
90
GmeeCL


 


1140
Q96QS1|TSN32_HUMAN
258
263
GpthCL


 


1141
Q96QU8|XPO6_HUMAN
413
418
GyfsCL


 


1142
Q96R30|OR2V2_HUMAN
103
108
GlfvCL


 


1143
Q96RV3|PCX1_HUMAN
696
701
GtvaCL


 


1144
Q96RW7|HMCN1_HUMAN
677
682
GiygCL


 


1145
Q96RW7|HMCN1_HUMAN
2546
2551
GrytCL


 


1146
Q96RW7|HMCN1_HUMAN
3595
3600
GrytCL


 


1147
Q96SM3|CPXM1_HUMAN
262
267
GgapCL


 


1148
Q96SQ9|CP2S1_HUMAN
436
441
GkrvCL


 


1149
Q96SU4|OSBL9_HUMAN
542
547
GcvsCL


 


1150
Q99250|SCN2A_HUMAN
955
960
GqtmCL


 


1151
Q99466|NOTC4_HUMAN
216
221
GsfqCL


 


1152
Q99466|NOTC4_HUMAN
375
380
GsfsCL


 


1153
Q99466|NOTC4_HUMAN
414
419
GstlCL


 


1154
Q99466|NOTC4_HUMAN
457
462
GsfnCL


 


1155
Q99466|NOTC4_HUMAN
609
614
GaffCL


 


1156
Q99466|NOTC4_HUMAN
787
792
GtfsCL


 


1157
Q99466|NOTC4_HUMAN
1121
1126
GgpdCL


 


1158
Q99466|NOTC4_HUMAN
1872
1877
GggaCL


 


1159
Q99558|M3K14_HUMAN
536
541
GhavCL


 


1160
Q99611|SPS2_HUMAN
373
378
GlliCL


 


1161
Q99678|GPR20_HUMAN
115
120
GargCL


 


1162
Q99741|CDC6_HUMAN
207
212
GktaCL


 


1163
Q99758|ABCA3_HUMAN
1590
1595
GqfkCL


 


1164
Q99797|PMIP_HUMAN
277
282
GqlkCL


 


1165
Q99848|EBP2_HUMAN
52
57
GlkqCL


 


1166
Q99867|TBB4Q_HUMAN
235
240
GvttCL


 


1167
Q99884|SC6A7_HUMAN
543
548
GllsCL


 


1168
Q99973|TEP1_HUMAN
1464
1469
GpfaCL


 


1169
Q99973|TEP1_HUMAN
1486
1491
GarlCL


 


1170
Q99973|TEP1_HUMAN
1720
1725
GisaCL


 


1171
Q99973|TEP1_HUMAN
2595
2600
GsusCL


 


1172
Q99996|AKAP9_HUMAN
3063
3068
GllnCL


 


1173
Q9BQ08|RSNB_HUMAN
2
7
GpssCL


 


1174
Q9BQG2|NUD12_HUMAN
348
353
GmftCL


 


1175
Q9BQR3|PRS27_HUMAN
231
236
GplvCL


 


1176
Q9BQS2|SYT15_HUMAN
23
28
GascCL


 


1177
Q9BRB3|PIGQ_HUMAN
373
378
GlsaCL


 


1178
Q9BRP4|WDR71_HUMAN
206
211
GrsaCL


 


1179
Q9BRZ2|TRI56_HUMAN
343
348
GpapCL


 


1180
Q9BS86|ZPBP1_HUMAN
346
351
GaktCL


 


1181
Q9BT40|SKIP_HUMAN
131
136
GvniCL


 


1182
Q9BT51|CU122_HUMAN
6
11
GfshCL


 


1183
Q9BTF0|THUM2_HUMAN
407
412
GikkCL


 


1184
Q9BTX1|NDC1_HUMAN
310
315
GsdeCL


 


1185
Q9BUY5|ZN426_HUMAN
14
19
GdpvCL


 


1186
Q9BUY5|ZN426_HUMAN
430
435
GypsCL


 


1187
Q9BV38|WDR18_HUMAN
81
86
GpvtCL


 


1188
Q9BV38|WDR18_HUMAN
139
144
GgkdCL


 


1189
Q9BV73|CP250_HUMAN
806
811
GevrCL


 


1190
Q9BV99|LRC61_HUMAN
113
118
GqlqCL


 


1191
Q9BVA1|TBB2B_HUMAN
235
240
GvttCL


 


1192
Q9BVH7|SIA7E_HUMAN
8
13
GlavCL


 


1193
Q9BVK2|ALG8_HUMAN
361
366
GflrCL


 


1194
Q9BWT7|CAR10_HUMAN
916
921
GkkhCL


 


1195
Q9BWU0|NADAP_HUMAN
185
190
GtsyCL


 


1196
Q9BWU0|NADAP_HUMAN
196
201
GcdvCL


 


1197
Q9BWV1|BOC_HUMAN
1053
1058
GppcCL


 


1198
Q9BXC9|BBS2_HUMAN
26
31
GthpCL


 


1199
Q9BXL6|CAR14_HUMAN
850
855
GfkkCL


 


1200
Q9BXM7|PINK1_HUMAN
408
413
GgngCL


 


1201
Q9BXR0|TGT_HUMAN
50
55
GcriCL


 


1202
Q9BXS4|TMM59_HUMAN
229
234
GflrCL


 


1203
Q9BXT5|TEX15_HUMAN
1099
1104
GekkCL


 


1204
Q9BXU8|FHL17_HUMAN
78
83
GghiCL


 


1205
Q9BY15|EMR3_HUMAN
562
567
GctwCL


 


1206
Q9BY41|HDAC8_HUMAN
283
288
GigkCL


 


1207
Q9BYB4|GNB1L_HUMAN
163
168
GmpmCL


 


1208
Q9BYE0|HES7_HUMAN
95
100
GfreCL


 


1209
Q9BYJ1|LOXE3_HUMAN
309
314
GqdtCL


 


1210
Q9BYK8|PR285_HUMAN
1908
1913
GfslCL


 


1211
Q9BYT1|CT059_HUMAN
398
403
GswtCL


 


1212
Q9BYX4|IFIH1_HUMAN
265
270
GsusCL


 


1213
Q9BZ11|ADA33_HUMAN
400
405
GggaCL


 


1214
Q9BZ76|CNTP3_HUMAN
509
514
GfqgCL


 


1215
Q9BZ76|CNTP3_HUMAN
1163
1168
GftgCL


 


1216
Q9BZC7|ABCA2_HUMAN
2262
2267
GrlrCL


 


1217
Q9BZF3|OSBL6_HUMAN
554
559
GrraCL


 


1218
Q9BZF9|UACA_HUMAN
79
84
GnleCL


 


1219
Q9BZF9|UACA_HUMAN
112
117
GhalCL


 


1220
Q9BZH6|BRWD2_HUMAN
79
84
GspyCL


 


1221
Q9BZS1|FOXP3_HUMAN
228
233
GraqCL


 


1222
Q9BZY9|TRI31_HUMAN
32
37
GhnfCL


 


1223
Q9BZZ2|SN_HUMAN
1507
1512
GmyhCL


 


1224
Q9C004|SPY4_HUMAN
197
202
GtcmCL


 


1225
Q9C0A0|CNTP4_HUMAN
1163
1168
GftgCL


 


1226
Q9C0C6|K1737_HUMAN
47
52
GsseCL


 


1227
Q9GZK3|OR2B2_HUMAN
108
113
GsteCL


 


1228
Q9GZR3|CFC1_HUMAN
144
149
GalhCL


 


1229
Q9GZY1|PBOV1_HUMAN
118
123
GlecCL


 


1230
Q9H013|ADA19_HUMAN
400
405
GggmCL


 


1231
Q9H093|NUAK2_HUMAN
587
592
GpgsCL


 


1232
Q9H0A0|NAT10_HUMAN
654
659
GrfpCL


 


1233
Q9H0B3|K1683_HUMAN
578
583
GkirCL


 


1234
Q9H0J9|PAR12_HUMAN
272
277
GdqiCL


 


1235
Q9H0M4|ZCPW1_HUMAN
249
254
GfgqCL


 


1236
Q9H172|ABCG4_HUMAN
588
593
GdltCL


 


1237
Q9H195|MUC3B_HUMAN
545
550
GqcaCL


 


1238
Q9H1B7|CN004_HUMAN
294
299
GgpaCL


 


1239
Q9H1D0|TRPV6_HUMAN
10
15
GlilCL


 


1240
Q9H1K4|GHC2_HUMAN
47
52
GmidCL


 


1241
Q9H1M3|DB129_HUMAN
23
28
GlrrCL


 


1242
Q9H1M4|DB127_HUMAN
50
55
GrycCL


 


1243
Q9H1P6|CT085_HUMAN
107
112
GlnkCL


 


1244
Q9H1R3|MYLK2_HUMAN
240
245
GqalCL


 


1245
Q9H1V8|S6A17_HUMAN
421
426
GldpCL


 


1246
Q9H221|ABCG8_HUMAN
421
426
GaeaCL


 


1247
Q9H228|EDG8_HUMAN
347
352
GlrrCL


 


1248
Q9H252|KCNH6_HUMAN
571
576
GfpeCL


 


1249
Q9H2D1|MFTC_HUMAN
64
69
GilhCL


 


1250
Q9H2G2|SLK_HUMAN
1208
1213
GeseCL


 


1251
Q9H2M9|RBGPR_HUMAN
387
392
GesiCL


 


1252
Q9H2S1|KCNN2_HUMAN
371
376
GkgvCL


 


1253
Q9H2X9|S12A5_HUMAN
602
607
GmslCL


 


1254
Q9H2Y7|ZF106_HUMAN
975
980
GegnCL


 


1255
Q9H324|ATS10_HUMAN
422
427
GlglCL


 


1256
Q9H324|ATS10_HUMAN
556
561
GgkyCL


 


1257
Q9H3D4|P73L_HUMAN
557
562
GcssCL


 


1258
Q9H3R1|NDST4_HUMAN
814
819
GktkCL


 


1259
Q9H4F1|SIA7D_HUMAN
29
34
GlplCL


 


1260
Q9H5U8|CX045_HUMAN
403
408
GfdsCL


 


1261
Q9H5V8|CDCP1_HUMAN
373
378
GcfvCL


 


1262
Q9H6E5|TUT1_HUMAN
15
20
GfrcCL


 


1263
Q9H6R4|NOL6_HUMAN
391
396
GislCL


 


1264
Q9H792|SG269_HUMAN
1661
1666
GilqCL


 


1265
Q9H7F0|AT133_HUMAN
109
114
GhavCL


 


1266
Q9H7M9|GI24_HUMAN
142
147
GlycCL


 


1267
Q9H808|TLE6_HUMAN
315
320
GpdaCL


 


1268
Q9H8X2|IPPK_HUMAN
110
115
GyamCL


 


1269
Q9H9S3|S61A2_HUMAN
143
148
GagiCL


 


1270
Q9HAF5|CO028_HUMAN
120
125
GvrmCL


 


1271
Q9HAS0|NJMU_HUMAN
123
128
GcyyCL


 


1272
Q9HAT1|LMA1L_HUMAN
8
13
GplfCL


 


1273
Q9HAV4|XPO5_HUMAN
266
271
GaaeCL


 


1274
Q9HAW7|UD17_HUMAN
510
515
GyrkCL


 


1275
Q9HAW8|UD110_HUMAN
510
515
GyrkCL


 


1276
Q9HAW9|UD18_HUMAN
510
515
GyrkCL


 


1277
Q9HBX8|LGR6_HUMAN
550
555
GvlgCL


 


1278
Q9HBZ2|ARNT2_HUMAN
295
300
GskyCL


 


1279
Q9HC07|TM165_HUMAN
138
143
GlmtCL


 


1280
Q9HC84|MUC5B_HUMAN
780
785
GklsCL


 


1281
Q9HC84|MUC5B_HUMAN
1281
1286
GlgaCL


 


1282
Q9HCC6|HES4_HUMAN
113
118
GfheCL


 


1283
Q9HCC9|ZFY28_HUMAN
555
560
GatnCL


 


1284
Q9HCE9|TM16H_HUMAN
541
546
GgrrCL


 


1285
Q9HCM2|PLXA4_HUMAN
990
995
GkqpCL


 


1286
Q9HCM4|E41L5_HUMAN
111
116
GspyCL


 


1287
Q9HCU4|CELR2_HUMAN
1308
1313
GgytCL


 


1288
Q9HCU4|CELR2_HUMAN
1757
1762
GfrgCL


 


1289
Q9HCU4|CELR2_HUMAN
1917
1922
GsptCL


 


1290
Q9NNW5|WDR6_HUMAN
460
465
GvvaCL


 


1291
Q9NP73|GT281_HUMAN
82
87
GagsCL


 


1292
Q9NP90|RAB9B_HUMAN
79
84
GadcCL


 


1293
Q9NPA1|KCMB3_HUMAN
121
126
GkypCL


 


1294
Q9NPA3|M1IP1_HUMAN
58
63
GsggCL


 


1295
Q9NPD7|NRN1_HUMAN
37
42
GfsdCL


 


1296
Q9NPF8|CENA2_HUMAN
41
46
GifiCL


 


1297
Q9NPG4|PCD12_HUMAN
807
812
GwdpCL


 


1298
Q9NPH5|NOX4_HUMAN
51
56
GlglCL


 


1299
Q9NQ25|SLAF7_HUMAN
3
8
GsptCL


 


1300
Q9NQ30|ESM1_HUMAN
125
130
GtgkCL


 


1301
Q9NQ75|CT032_HUMAN
50
55
GwwkCL


 


1302
Q9NQB0|TF7L2_HUMAN
492
497
GegsCL


 


1303
Q9NQQ7|S35C2_HUMAN
302
307
GfalCL


 


1304
Q9NQS5|GPR84_HUMAN
195
200
GifyCL


 


1305
Q9NQU5|PAK6_HUMAN
662
667
GlpeCL


 


1306
Q9NR09|BIRC6_HUMAN
511
516
GanpCL


 


1307
Q9NR61|DLL4_HUMAN
204
209
GnlsCL


 


1308
Q9NR63|CP26B_HUMAN
437
442
GvrtCL


 


1309
Q9NR81|ARHG3_HUMAN
203
208
GwlpCL


 


1310
Q9NR99|MXRA5_HUMAN
2414
2419
GnytCL


 


1311
Q9NRI5|DISC1_HUMAN
23
28
GsrdCL


 


1312
Q9NRX5|SERC1_HUMAN
19
24
GsapCL


 


1313
Q9NS15|LTBP3_HUMAN
846
851
GsyrCL


 


1314
Q9NS40|KCNH7_HUMAN
722
727
GfpeCL


 


1315
Q9NS62|THSD1_HUMAN
419
424
GislCL


 


1316
Q9NSD7|RL3R1_HUMAN
243
248
GeelCL


 


1317
Q9NSI6|BRWD1_HUMAN
204
209
GsddCL


 


1318
Q9NSN8|SNTG1_HUMAN
242
247
GiiqCL


 


1319
Q9NST1|ADPN_HUMAN
24
29
GatrCL


 


1320
Q9NST1|ADPN_HUMAN
97
102
GlckCL


 


1321
Q9NT68|TEN2_HUMAN
858
863
GlvdCL


 


1322
Q9NU22|MDN1_HUMAN
427
432
GrgdCL


 


1323
Q9NUB4|CT141_HUMAN
156
161
GlafCL


 


1324
Q9NUP1|CNO_HUMAN
67
72
GyaaCL


 


1325
Q9NVE7|PANK4_HUMAN
304
309
GqlaCL


 


1326
Q9NVG8|TBC13_HUMAN
38
43
GglrCL


 


1327
Q9NVX2|NLE1_HUMAN
474
479
GkdkCL


 


1328
Q9NW08|RPC2_HUMAN
765
770
GfgrCL


 


1329
Q9NWT1|PK1IP_HUMAN
83
88
GtitCL


 


1330
Q9NWU5|RM22_HUMAN
142
147
GrgqCL


 


1331
Q9NWZ3|IRAK4_HUMAN
255
260
GddlCL


 


1332
Q9NX02|NALP2_HUMAN
139
144
GnviCL


 


1333
Q9NXJ0|M4A12_HUMAN
106
111
GivlCL


 


1334
Q9NXR5|ANR10_HUMAN
69
74
GkleCL


 


1335
Q9NXR5|ANR10_HUMAN
103
108
GhpqCL


 


1336
Q9NXS3|BTBD5_HUMAN
293
298
GlfaCL


 


1337
Q9NXW9|ALKB4_HUMAN
19
24
GirtCL


 


1338
Q9NY15|STAB1_HUMAN
122
127
GhgtCL


 


1339
Q9NY15|STAB1_HUMAN
177
182
GdgsCL


 


1340
Q9NY15|STAB1_HUMAN
752
757
GngaCL


 


1341
Q9NY15|STAB1_HUMAN
1256
1261
GssrCL


 


1342
Q9NY15|STAB1_HUMAN
1991
1996
GsgqCL


 


1343
Q9NY15|STAB1_HUMAN
2250
2255
GfhlCL


 


1344
Q9NY33|DPP3_HUMAN
515
520
GlylCL


 


1345
Q9NY35|CLDND_HUMAN
213
218
GwsfCL


 


1346
Q9NY46|SCN3A_HUMAN
956
961
GqtmCL


 


1347
Q9NY91|SC5A4_HUMAN
507
512
GtgsCL


 


1348
Q9NY99|SNTG2_HUMAN
14
19
GrqgCL


 


1349
Q9NYJ7|DLL3_HUMAN
235
240
GecrCL


 


1350
Q9NYQ6|CELR1_HUMAN
168
173
GrpiCL


 


1351
Q9NYQ7|CELR3_HUMAN
2070
2075
GsdsCL


 


1352
Q9NYQ8|FAT2_HUMAN
3908
3913
GfegCL


 


1353
Q9NYQ8|FAT2_HUMAN
4285
4290
GggpCL


 


1354
Q9NYW6|TA2R3_HUMAN
104
109
GvlyCL


 


1355
Q9NZ56|FMN2_HUMAN
1694
1699
GkeqCL


 


1356
Q9NZ71|RTEL1_HUMAN
47
52
GktlCL


 


1357
Q9NZ94|NLGN3_HUMAN
19
24
GrslCL


 


1358
Q9NZH0|GPC5B_HUMAN
164
169
GlalCL


 


1359
Q9NZH7|IL1F8_HUMAN
68
73
GkdlCL


 


1360
Q9NZL3|ZN224_HUMAN
550
555
GwasCL


 


1361
Q9NZR2|LRP1B_HUMAN
866
871
GdddCL


 


1362
Q9NZR2|LRP1B_HUMAN
2987
2992
GtykCL


 


1363
Q9NZV5|SEPN1_HUMAN
273
278
GavaCL


 


1364
Q9P0K1|ADA22_HUMAN
429
434
GggaCL


 


1365
Q9P0K7|RAI14_HUMAN
64
69
GhveCL


 


1366
Q9P0L1|ZN167_HUMAN
617
622
GlskCL


 


1367
Q9P0M9|RM27_HUMAN
84
89
GknkCL


 


1368
Q9P0U3|SENP1_HUMAN
531
536
GvhwCL


 


1369
Q9P0X4|CAC1I_HUMAN
290
295
GrecCL


 


1370
Q9P203|BTBD7_HUMAN
265
270
GnqnCL


 


1371
Q9P255|ZN492_HUMAN
143
148
GlnqCL


 


1372
Q9P273|TEN3_HUMAN
142
147
GrssCL


 


1373
Q9P273|TEN3_HUMAN
1590
1595
GtngCL


 


1374
Q9P275|UBP36_HUMAN
824
829
GsetCL


 


1375
Q9P283|SEM5B_HUMAN
589
594
GgldCL


 


1376
Q9P283|SEM5B_HUMAN
887
892
GediCL


 


1377
Q9P298|HIG1B_HUMAN
34
39
GlggCL


 


1378
Q9P2B2|FPRP_HUMAN
844
849
GllsCL


 


1379
Q9P2C4|TM181_HUMAN
406
411
GerkCL


 


1380
Q9P2E3|ZNFX1_HUMAN
1162
1167
GqlfCL


 


1381
Q9P2I0|CPSF2_HUMAN
759
764
GlegCL


 


1382
Q9P2J9|PDP2_HUMAN
125
130
GvasCL


 


1383
Q9P2J9|PDP2_HUMAN
298
303
GmwsCL


 


1384
Q9P2N4|ATS9_HUMAN
490
495
GygeCL


 


1385
Q9P2P6|STAR9_HUMAN
715
720
GeadCL


 


1386
Q9P2R3|ANFY1_HUMAN
720
725
GpggCL


 


1387
Q9P2R7|SUCB1_HUMAN
316
321
GnigCL


 


1388
Q9P2S2|NRX2A_HUMAN
1061
1066
GfqgCL


 


1389
Q9UBD9|CLCF1_HUMAN
10
15
GmlaCL


 


1390
Q9UBE0|ULE1A_HUMAN
338
343
GiveCL


 


1391
Q9UBG0|MRC2_HUMAN
50
55
GlqgCL


 


1392
Q9UBG0|MRC2_HUMAN
89
94
GtmqCL


 


1393
Q9UBG0|MRC2_HUMAN
938
943
GdqrCL


 


1394
Q9UBG7|RBPSL_HUMAN
56
61
GvrrCL


 


1395
Q9UBG7|RBPSL_HUMAN
326
331
GtylCL


 


1396
Q9UBH0|IL1F5_HUMAN
63
68
GgsqCL


 


1397
Q9UBM4|OPT_HUMAN
124
129
GlptCL


 


1398
Q9UBP5|HEY2_HUMAN
125
130
GfreCL


 


1399
Q9UBS8|RNF14_HUMAN
258
263
GqvqCL


 


1400
Q9UBY5|EDG7_HUMAN
37
42
GtffCL


 


1401
Q9UBY8|CLN8_HUMAN
145
150
GflgCL


 


1402
Q9UDX3|S14L4_HUMAN
250
255
GnpkCL


 


1403
Q9UDX3|S14L4_HUMAN
351
356
GsltCL


 


1404
Q9UDX4|S14L3_HUMAN
250
255
GnpkCL


 


1405
Q9UGF7|O12D3_HUMAN
62
67
GnlsCL


 


1406
Q9UGI6|KCNN3_HUMAN
525
530
GkgvCL


 


1407
Q9UGU5|HM2L1_HUMAN
567
572
GplaCL


 


1408
Q9UHA7|IL1F6_HUMAN
69
74
GlnlCL


 


1409
Q9UHC6|CNTP2_HUMAN
1174
1179
GftgCL


 


1410
Q9UHD0|IL19_HUMAN
24
29
GlrrCL


 


1411
Q9UHI8|ATS1_HUMAN
458
463
GhgeCL


 


1412
Q9UHW9|S12A6_HUMAN
687
692
GmsiCL


 


1413
Q9UHX3|EMR2_HUMAN
742
747
GctwCL


 


1414
Q9UIA9|XPO7_HUMAN
933
938
GccsCL


 


1415
Q9UIE0|N230_HUMAN
286
291
GksfCL


 


1416
Q9UIF8|BAZ2B_HUMAN
627
632
GmqwCL


 


1417
Q9UIF9|BAZ2A_HUMAN
1006
1011
GpeeCL


 


1418
Q9UIH9|KLF15_HUMAN
117
122
GehfCL


 


1419
Q9UIR0|BTNL2_HUMAN
337
342
GqyrCL


 


1420
Q9UK10|ZN225_HUMAN
466
471
GwasCL


 


1421
Q9UK11|ZN223_HUMAN
294
299
GksfCL


 


1422
Q9UK12|ZN222_HUMAN
263
268
GksfCL


 


1423
Q9UK13|ZN221_HUMAN
488
493
GwasCL


 


1424
Q9UK13|ZN221_HUMAN
572
577
GwasCL


 


1425
Q9UK99|FBX3_HUMAN
189
194
GlkyCL


 


1426
Q9UKB1|FBW1B_HUMAN
281
286
GsvlCL


 


1427
Q9UKP4|ATS7_HUMAN
443
448
GwglCL


 


1428
Q9UKP5|ATS6_HUMAN
545
550
GgkyCL


 


1429
Q9UKQ2|ADA28_HUMAN
500
505
GkghCL


 


1430
Q9UKU0|ACSL6_HUMAN
104
109
GngpCL


 


1431
Q9UL25|RAB21_HUMAN
121
126
GneiCL


 


1432
Q9ULB1|NRX1A_HUMAN
1048
1053
GfqgCL


 


1433
Q9ULL4|PLXB3_HUMAN
1191
1196
GrgeCL


 


1434
Q9ULV0|MYO5B_HUMAN
1496
1501
GtvpCL


 


1435
Q9UM47|NOTC3_HUMAN
1228
1233
GgfrCL


 


1436
Q9UM82|SPAT2_HUMAN
37
42
GsdeCL


 


1437
Q9UMF0|ICAM5_HUMAN
879
884
GeavCL


 


1438
Q9UMW8|UBP18_HUMAN
61
66
GqtcCL


 


1439
Q9UNA0|ATS5_HUMAN
467
472
GhgnCL


 


1440
Q9UNA0|ATS5_HUMAN
525
530
GqmvCL


 


1441
Q9UNI1|ELA1_HUMAN
208
213
GplhCL


 


1442
Q9UP79|ATS8_HUMAN
421
426
GhgdCL


 


1443
Q9UP79|ATS8_HUMAN
562
567
GgryCL


 


1444
Q9UP95|S12A4_HUMAN
622
627
GmslCL


 


1445
Q9UPA5|BSN_HUMAN
1765
1770
GspvCL


 


1446
Q9UPZ6|THS7A_HUMAN
881
886
GiheCL


 


1447
Q9UQ05|KCNH4_HUMAN
213
218
GgsrCL


 


1448
Q9UQ49|NEUR3_HUMAN
380
385
GlfgCL


 


1449
Q9UQ52|CNTN6_HUMAN
96
101
GmyqCL


 


1450
Q9UQD0|SCN8A_HUMAN
949
954
GqamCL


 


1451
Q9Y219|JAG2_HUMAN
907
912
GwkpCL


 


1452
Q9Y236|OSGI2_HUMAN
480
485
GvtrCL


 


1453
Q9Y263|PLAP_HUMAN
721
726
GkaqCL


 


1454
Q9Y278|OST2_HUMAN
51
56
GaprCL


 


1455
Q9Y297|FBW1A_HUMAN
344
349
GsvlCL


 


1456
Q9Y2H6|FNDC3_HUMAN
790
795
GivtCL


 


1457
Q9Y2L6|FRM4B_HUMAN
871
876
GsqrCL


 


1458
Q9Y2P5|S27A5_HUMAN
345
350
GilgCL


 


1459
Q9Y2P5|S27A5_HUMAN
452
457
GkmsCL


 


1460
Q9Y2Q1|ZN257_HUMAN
132
137
GlnqCL


 


1461
Q9Y2T5|GPR52_HUMAN
205
210
GfivCL


 


1462
Q9Y385|UB2J1_HUMAN
87
92
GkkiCL


 


1463
Q9Y3B6|CN122_HUMAN
38
43
GeclCL


 


1464
Q9Y3C8|UFC1_HUMAN
112
117
GgkiCL


 


1465
Q9Y3I1|FBX7_HUMAN
71
76
GdliCL


 


1466
Q9Y3N9|OR2W1_HUMAN
108
113
GsveCL


 


1467
Q9Y3R4|NEUR2_HUMAN
160
165
GpghCL


 


1468
Q9Y3S2|ZN330_HUMAN
182
187
GqhsCL


 


1469
Q9Y485|DMXL1_HUMAN
187
192
GkddCL


 


1470
Q9Y485|DMXL1_HUMAN
2862
2867
XrnvCL


 


1471
Q9Y493|ZAN_HUMAN
1152
1157
GtatCL


 


1472
Q9Y4C0|NRX3A_HUMAN
1014
1019
GfqgCL


 


1473
Q9Y4F1|FARP1_HUMAN
820
825
GvphCL


 


1474
Q9Y4K1|AIM1_HUMAN
1473
1478
GhypCL


 


1475
Q9Y4W6|AFG32_HUMAN
31
36
GeqpCL


 


1476
Q9Y535|RPC8_HUMAN
43
48
GlciCL


 


1477
Q9Y561|LRP12_HUMAN
241
246
GnidCL


 


1478
Q9Y574|ASB4_HUMAN
86
91
GhveCL


 


1479
Q9Y575|ASB3_HUMAN
291
296
GhedCL


 


1480
Q9Y5F7|PCDGL_HUMAN
729
734
GtcaCL


 


1481
Q9Y5J3|HEY1_HUMAN
126
131
GfreCL


 


1482
Q9Y5N5|HEMK2_HUMAN
45
50
GveiCL


 


1483
Q9Y5Q5|CORIN_HUMAN
424
429
GdqrCL


 


1484
Q9Y5R5|DMRT2_HUMAN
130
135
GvvsCL


 


1485
Q9Y5R6|DMRT1_HUMAN
153
158
GsnpCL


 


1486
Q9Y5S2|MRCKB_HUMAN
1374
1379
GsvqCL


 


1487
Q9Y5W8|SNX13_HUMAN
73
78
GvpkCL


 


1488
Q9Y616|IRAK3_HUMAN
395
400
GldsCL


 


1489
Q9Y644|RFNG_HUMAN
203
208
GagfCL


 


1490
Q9Y662|OST3B_HUMAN
7
12
GgrsCL


 


1491
Q9Y666|S12A7_HUMAN
622
627
GmslCL


 


1492
Q9Y6H5|SNCAP_HUMAN
361
366
GhaeCL


 


1493
Q9Y6I4|UBP3_HUMAN
449
454
GpesCL


 


1494
Q9Y6N6|LAMC3_HUMAN
885
890
GqcsCL


 


1495
Q9Y6R1|S4A4_HUMAN
512
517
GaifCL


 


1496
Q9Y6R7|FCGBP_HUMAN
1661
1666
GqgvCL


 


1497
Q9Y6R7|FCGBP_HUMAN
2388
2393
GqcgCL


 


1498
Q9Y6R7|FCGBP_HUMAN
2862
2867
GqgvCL


 


1499
Q9Y6R7|FCGBP_HUMAN
3589
3594
GqcgCL


 


1500
Q9Y6R7|FCGBP_HUMAN
4063
4068
GqgvCL


 


1501
Q9Y6R7|FCGBP_HUMAN
4790
4795
GqcgCL


 


1502
Q9Y6R7|FCGBP_HUMAN
4852
4857
GcgrCL


 


1503
Q9Y6R7|FCGBP_HUMAN
5032
5037
GcpvCL
















TABLE 5







Collagens


Motif: C-N-X(3)-V-C


Number of Locations: 24


Number of Different Proteins: 24











SEQ
Accession
First
Last



ID
Number|Protein
Amino
Amino



NO:
Name
acid
acid
Sequence














1504
O14514|BAI1_HUMAN
400
406
CNnsaVC


 


1505
O75093|SLIT1_HUMAN
507
513
CNsdvVC


 


1506
O75534|CSDE1_HUMAN
733
739
CNvwrVC


 


1507
P02462|CO4A1_HUMAN
1505
1511
CNinnVC


 


1508
P08572|CO4A2_HUMAN
1549
1555
CNpgdVC


 


1509
P09758|TACD2_HUMAN
119
125
CNqtsVC


 


1510
P25391|LAMA1_HUMAN
751
757
CNvhgVC


 


1511
P29400|CO4A5_HUMAN
1521
1527
CNinnVC


 


1512
P53420|CO4A4_HUMAN
1525
1531
CNihqVC


 


1513
P83110|HTRA3_HUMAN
48
54
CNcclVC


 


1514
Q01955|CO4A3_HUMAN
1505
1511
CNvndVC


 


1515
Q13625|ASPP2_HUMAN
1002
1008
CNnvqVC


 


1516
Q13751|LAMB3_HUMAN
572
578
CNrypVC


 


1517
Q14031|CO4A6_HUMAN
1527
1533
CNineVC


 


1518
Q8WWQ8|STAB2_HUMAN
1970
1976
CNnrgVC


 


1519
Q96GX1|TECT2_HUMAN
642
648
CNrneVC


 


1520
Q99965|ADAM2_HUMAN
621
627
CNdrgVC


 


1521
Q9BX93|PG12B_HUMAN
112
118
CNqldVC


 


1522
Q9BYD5|CNFN_HUMAN
32
38
CNdmpVC


 


1523
Q9H013|ADA19_HUMAN
659
665
CNghgVC


 


1524
Q9HBG6|IF122_HUMAN
436
442
CNllvVC


 


1525
Q9P2R7|SUCB1_HUMAN
152
158
CNqvlVC


 


1526
Q9UBX1|CATF_HUMAN
89
95
CNdpmVC


 


1527
Q9UKF2|ADA30_HUMAN
638
644
CNtrgVC
















TABLE 6







Collagens


Motif: P-F-X2-C


Number of Locations: 306


Number of Different Proteins: 288











SEQ
Accession
First
Last



ID
Number|Protein
Amino
Amino



NO:
Name
acid
acid
Sequence














1528
O00116|ADAS_HUMAN
561
565
PFstC


 


1529
O00182|LEG9_HUMAN
98
102
PFdlC


 


1530
O00206|TLR4_HUMAN
702
706
PFqlC


 


1531
O00270|GPR31_HUMAN
2
6
PFpnC


 


1532
O00398|P2Y10_HUMAN
288
292
PFclC


 


1533
O00507|USP9Y_HUMAN
259
263
PFgqC


 


1534
O14646|CHD1_HUMAN
450
454
PFkdC


 


1535
O14843|FFAR3_HUMAN
84
88
PFilC


 


1536
O14978|ZN263_HUMAN
547
551
PFseC


 


1537
O15015|ZN646_HUMAN
880
884
PFlcC


 


1538
O15031|PLXB2_HUMAN
611
615
PFydC


 


1539
O15037|K0323_HUMAN
423
427
PFtlC


 


1540
O15453|NBR2_HUMAN
9
13
PFlpC


 


1541
O15529|GPR42_HUMAN
84
88
PFilC


 


1542
O43556|SGCE_HUMAN
207
211
PFssC


 


1543
O60299|K0552_HUMAN
308
312
PFaaC


 


1544
O60343|TBCD4_HUMAN
89
93
PFlrC


 


1545
O60431|OR1I1_HUMAN
93
97
PFvgC


 


1546
O60449|LY75_HUMAN
1250
1254
PFqnC


 


1547
O60481|ZIC3_HUMAN
331
335
PFpgC


 


1548
O60486|PLXC1_HUMAN
618
622
PFtaC


 


1549
O60494|CUBN_HUMAN
3302
3306
PFsiC


 


1550
O60603|TLR2_HUMAN
669
673
PFklC


 


1551
O60656|UD19_HUMAN
149
153
PFdnC


 


1552
O60706|ABCC9_HUMAN
627
631
PFesC


 


1553
O75152|ZC11A_HUMAN
23
27
PFrhC


 


1554
O75197|LRP5_HUMAN
317
321
PFytC


 


1555
O75419|CC45L_HUMAN
444
448
PFlyC


 


1556
O75473|LGR5_HUMAN
547
551
PFkpC


 


1557
O75478|TAD2L_HUMAN
38
42
PFflC


 


1558
O75581|LRP6_HUMAN
304
308
PFyqC


 


1559
O75794|CD123_HUMAN
147
151
PFihC


 


1560
O75882|ATRN_HUMAN
969
973
PFgqC


 


1561
O76031|CLPX_HUMAN
313
317
PFaiC


 


1562
O95006|OR2F2_HUMAN
93
97
PFqsC


 


1563
O95007|OR6B1_HUMAN
285
289
PFiyC


 


1564
O95149|SPN1_HUMAN
195
199
PFydC


 


1565
O95202|LETM1_HUMAN
51
55
PFgcC


 


1566
O95409|ZIC2_HUMAN
336
340
PFpgC


 


1567
O95450|ATS2_HUMAN
569
573
PFgsC


 


1568
O95759|TBCD8_HUMAN
67
71
PFsrC


 


1569
O95841|ANGL1_HUMAN
276
280
PFkdC


 


1570
O95886|DLGP3_HUMAN
98
102
PFdtC


 


1571
P02461|CO3A1_HUMAN
80
84
PFgeC


 


1572
P02462|CO4A1_HUMAN
1501
1505
PFlfC


 


1573
P02462|CO4A1_HUMAN
1612
1616
PFieC


 


1574
P08151|GLI1_HUMAN
173
177
PFptC


 


1575
P08572|CO4A2_HUMAN
1545
1549
PFlyC


 


1576
P08572|CO4A2_HUMAN
1654
1658
PFieC


 


1577
P08581|MET_HUMAN
534
538
PFvqC


 


1578
P09172|DOPO_HUMAN
136
140
PFgtC


 


1579
P0C0L4|CO4A_HUMAN
731
735
PFlsC


 


1580
P0C0L5|CO4B_HUMAN
731
735
PFlsC


 


1581
P15309|PPAP_HUMAN
157
161
PFrnC


 


1582
P17021|ZNF17_HUMAN
350
354
PFycC


 


1583
P18084|ITB5_HUMAN
546
550
PFceC


 


1584
P20645|MPRD_HUMAN
3
7
PFysC


 


1585
P20851|C4BB_HUMAN
130
134
PFpiC


 


1586
P20933|ASPG_HUMAN
13
17
PFllC


 


1587
P21673|SAT1_HUMAN
50
54
PFyhC


 


1588
P21854|CD72_HUMAN
222
226
PFftC


 


1589
P22309|UD11_HUMAN
152
156
PFlpC


 


1590
P22362|CCL1_HUMAN
29
33
PFsrC


 


1591
P22681|CBL_HUMAN
417
421
PFcrC


 


1592
P23942|RDS_HUMAN
210
214
PFscC


 


1593
P24043|LAMA2_HUMAN
2679
2683
PFegC


 


1594
P24043|LAMA2_HUMAN
3083
3087
PFrgC


 


1595
P24903|CP2F1_HUMAN
483
487
PFqlC


 


1596
P25098|ARBK1_HUMAN
252
256
PFivC


 


1597
P25490|TYY1_HUMAN
386
390
PFdgC


 


1598
P25929|NPY1R_HUMAN
117
121
PFvqC


 


1599
P26718|NKG2D_HUMAN
52
56
PFffC


 


1600
P26927|HGFL_HUMAN
439
443
PFdyC


 


1601
P27987|IP3KB_HUMAN
869
873
PFfkC


 


1602
P29400|CO4A5_HUMAN
1517
1521
PFmfC


 


1603
P29400|CO4A5_HUMAN
1628
1632
PFieC


 


1604
P34896|GLYC_HUMAN
244
248
PFehC


 


1605
P35504|UD15_HUMAN
153
157
PFhlC


 


1606
P35523|CLCN1_HUMAN
26
30
PFehC


 


1607
P35626|ARBK2_HUMAN
252
256
PFivC


 


1608
P36383|CXA7_HUMAN
205
209
PFyvC


 


1609
P36508|ZNF76_HUMAN
258
262
PFegC


 


1610
P36509|UD12_HUMAN
149
153
PFdnC


 


1611
P36894|BMR1A_HUMAN
57
61
PFlkC


 


1612
P41180|CASR_HUMAN
538
542
PFsnC


 


1613
P42338|PK3CB_HUMAN
650
654
PFldC


 


1614
P42575|CASP2_HUMAN
141
145
PFpvC


 


1615
P45974|UBP5_HUMAN
528
532
PFssC


 


1616
P46531|NOTC1_HUMAN
1411
1415
PFyrC


 


1617
P48637|GSHB_HUMAN
405
409
PFenC


 


1618
P49257|LMAN1_HUMAN
471
475
PFpsC


 


1619
P49888|ST1E1_HUMAN
79
83
PFleC


 


1620
P50052|AGTR2_HUMAN
315
319
PFlyC


 


1621
P50876|UB7I4_HUMAN
273
277
PFvlC


 


1622
P51606|RENBP_HUMAN
376
380
PFkgC


 


1623
P51617|IRAK1_HUMAN
195
199
PFpfC


 


1624
P51689|ARSD_HUMAN
581
585
PFcsC


 


1625
P51690|ARSE_HUMAN
576
580
PFplC


 


1626
P52740|ZN132_HUMAN
369
373
PFecC


 


1627
P52747|ZN143_HUMAN
318
322
PFegC


 


1628
P53420|CO4A4_HUMAN
1521
1525
PFayC


 


1629
P53420|CO4A4_HUMAN
1630
1634
PFleC


 


1630
P53621|COPA_HUMAN
1165
1169
PFdiC


 


1631
P54198|HIRA_HUMAN
215
219
PFdeC


 


1632
P54793|ARSF_HUMAN
570
574
PFclC


 


1633
P54802|ANAG_HUMAN
401
405
PFiwC


 


1634
P55157|MTP_HUMAN
823
827
PFlvC


 


1635
P62079|TSN5_HUMAN
183
187
PFscC


 


1636
P78357|CNTP1_HUMAN
926
930
PFvgC


 


1637
P78527|PRKDC_HUMAN
2853
2857
PFvsC


 


1638
P81133|SIM1_HUMAN
200
204
PFdgC


 


1639
P98088|MUC5A_HUMAN
290
294
PFkmC


 


1640
Q01955|CO4A3_HUMAN
1501
1505
PFlfC


 


1641
Q01955|CO4A3_HUMAN
1612
1616
PFleC


 


1642
Q02817|MUC2_HUMAN
597
601
PFgrC


 


1643
Q02817|MUC2_HUMAN
1375
1379
PFglC


 


1644
Q02817|MUC2_HUMAN
4916
4920
PFywC


 


1645
Q03395|ROM1_HUMAN
213
217
PFscC


 


1646
Q07912|ACK1_HUMAN
293
297
PFawC


 


1647
Q12830|BPTF_HUMAN
2873
2877
PFyqC


 


1648
Q12836|ZP4_HUMAN
238
242
PFtsC


 


1649
Q12866|MERTK_HUMAN
313
317
PFrnC


 


1650
Q12950|FOXD4_HUMAN
291
295
PFpcC


 


1651
Q12968|NFAC3_HUMAN
327
331
PFqyC


 


1652
Q13191|CBLB_HUMAN
409
413
PFcrC


 


1653
Q13258|PD2R_HUMAN
4
8
PFyrC


 


1654
Q13356|PPIL2_HUMAN
38
42
PFdhC


 


1655
Q13607|OR2F1_HUMAN
93
97
PFqsC


 


1656
Q13753|LAMC2_HUMAN
409
413
PFgtC


 


1657
Q13936|CAC1C_HUMAN
2179
2183
PFvnC


 


1658
Q14031|CO4A6_HUMAN
1523
1527
PFiyC


 


1659
Q14031|CO4A6_HUMAN
1632
1636
PFieC


 


1660
Q14137|BOP1_HUMAN
400
404
PFptC


 


1661
Q14330|GPR18_HUMAN
247
251
PFhiC


 


1662
Q14643|ITPR1_HUMAN
526
530
PFtdC


 


1663
Q15042|RB3GP_HUMAN
267
271
PFgaC


 


1664
Q15389|ANGP1_HUMAN
282
286
PFrdC


 


1665
Q15583|TGIF_HUMAN
269
273
PFhsC


 


1666
Q15583|TGIF_HUMAN
314
318
PFslC


 


1667
Q15761|NPY5R_HUMAN
128
132
PFlqC


 


1668
Q15915|ZIC1_HUMAN
305
309
PFpgC


 


1669
Q16363|LAMA4_HUMAN
1788
1792
PFtgC


 


1670
Q16572|VACHT_HUMAN
517
521
PFdeC


 


1671
Q16586|SGCA_HUMAN
205
209
PFstC


 


1672
Q16773|KAT1_HUMAN
123
127
PFfdC


 


1673
Q16878|CDO1_HUMAN
160
164
PFdtC


 


1674
Q2TBC4|CF049_HUMAN
298
302
PFstC


 


1675
Q49AM1|MTER3_HUMAN
28
32
PFlaC


 


1676
Q53FE4|CD017_HUMAN
77
81
PFanC


 


1677
Q53G59|KLH12_HUMAN
240
244
PFirC


 


1678
Q53T03|RBP22_HUMAN
517
521
PFpvC


 


1679
Q5IJ48|CRUM2_HUMAN
762
766
PFrgC


 


1680
Q5T442|CXA12_HUMAN
241
245
PFfpC


 


1681
Q5VYX0|RENAL_HUMAN
310
314
PFlaC


 


1682
Q5W0N0|CI057_HUMAN
89
93
PFhgC


 


1683
Q6NSW7|NANP8_HUMAN
239
243
PFynC


 


1684
Q6P2Q9|PRP8_HUMAN
1892
1896
PFqaC


 


1685
Q6PRD1|GP179_HUMAN
232
236
PFleC


 


1686
Q6TCH4|PAQR6_HUMAN
95
99
PFasC


 


1687
Q6UB98|ANR12_HUMAN
1949
1953
PFsaC


 


1688
Q6UB99|ANR11_HUMAN
2552
2556
PFsaC


 


1689
Q6UXZ4|UNC5D_HUMAN
766
770
PFtaC


 


1690
Q7Z434|MAVS_HUMAN
431
435
PFsgC


 


1691
Q7Z6J6|FRMD5_HUMAN
87
91
PFtmC


 


1692
Q7Z7G8|VP13B_HUMAN
441
445
PFfdC


 


1693
Q7Z7G8|VP13B_HUMAN
1423
1427
PFrnC


 


1694
Q7Z7M1|GP144_HUMAN
352
356
PFlcC


 


1695
Q86SJ6|DSG4_HUMAN
523
527
PFtfC


 


1696
Q86SQ6|GP123_HUMAN
863
867
PFiiC


 


1697
Q86T65|DAAM2_HUMAN
548
552
PFacC


 


1698
Q86V97|KBTB6_HUMAN
355
359
PFlcC


 


1699
Q86XI2|CNDG2_HUMAN
1043
1047
PFsrC


 


1700
Q86YT6|MIB1_HUMAN
909
913
PFimC


 


1701
Q8IUH2|CREG2_HUMAN
152
156
PFgnC


 


1702
Q8IWU5|SULF2_HUMAN
745
749
PFcaC


 


1703
Q8IWV8|UBR2_HUMAN
1514
1518
PFlkC


 


1704
Q8IWX5|SGPP2_HUMAN
257
261
PFflC


 


1705
Q8IX07|FOG1_HUMAN
293
297
PFpqC


 


1706
Q8IX29|FBX16_HUMAN
287
291
PFplC


 


1707
Q8IXT2|DMRTD_HUMAN
224
228
PFttC


 


1708
Q8IZF5|GP113_HUMAN
62
66
PFpaC


 


1709
Q8IZQ8|MYCD_HUMAN
403
407
PFqdC


 


1710
Q8IZW8|TENS4_HUMAN
423
427
PFttC


 


1711
Q8N0W3|FUK_HUMAN
100
104
PFddC


 


1712
Q8N122|RPTOR_HUMAN
1033
1037
PFtpC


 


1713
Q8N1G1|REXO1_HUMAN
278
282
PFgsC


 


1714
Q8N1G2|K0082_HUMAN
790
794
PFhiC


 


1715
Q8N201|INT1_HUMAN
1573
1577
PFpaC


 


1716
Q8N475|FSTL5_HUMAN
61
65
PFgsC


 


1717
Q8N567|ZCHC9_HUMAN
182
186
PFakC


 


1718
Q8N7R0|NANG2_HUMAN
166
170
PFynC


 


1719
Q8N8U9|BMPER_HUMAN
234
238
PFgsC


 


1720
Q8N9L1|ZIC4_HUMAN
207
211
PFpgC


 


1721
Q8NB16|MLKL_HUMAN
411
415
PFqgC


 


1722
Q8NG11|TSN14_HUMAN
183
187
PFscC


 


1723
Q8NGC3|O10G2_HUMAN
98
102
PFggC


 


1724
Q8NGC4|O10G3_HUMAN
94
98
PFggC


 


1725
Q8NGJ1|OR4D6_HUMAN
165
169
PFpfC


 


1726
Q8NH69|OR5W2_HUMAN
93
97
PFygC


 


1727
Q8NH85|OR5R1_HUMAN
93
97
PFhaC


 


1728
Q8NHU2|CT026_HUMAN
442
446
PFntC


 


1729
Q8NHY3|GA2L2_HUMAN
359
363
PFlrC


 


1730
Q8N151|BORIS_HUMAN
369
373
PFqcC


 


1731
Q8TCB0|IFI44_HUMAN
246
250
PFilC


 


1732
Q8TCE9|PPL13_HUMAN
88
92
PFelC


 


1733
Q8TCT7|PSL1_HUMAN
275
279
PFgkC


 


1734
Q8TD94|KLF14_HUMAN
198
202
PFpgC


 


1735
Q8TF76|HASP_HUMAN
474
478
PFshC


 


1736
Q8WW14|CJ082_HUMAN
22
26
PFlsC


 


1737
Q8WW38|FOG2_HUMAN
299
303
PFpqC


 


1738
Q8WWG1|NRG4_HUMAN
32
36
PFcrC


 


1739
Q8WWZ7|ABCA5_HUMAN
361
365
PFchC


 


1740
Q8WXT5|FX4L4_HUMAN
295
299
PFpcC


 


1741
Q8WYR1|PI3R5_HUMAN
814
818
PFavC


 


1742
Q8WZ42|TITIN_HUMAN
31091
31095
PFpiC


 


1743
Q8WZ60|KLHL6_HUMAN
432
436
PFhnC


 


1744
Q92485|ASM3B_HUMAN
41
45
PFqvC


 


1745
Q92793|CBP_HUMAN
1279
1283
PFvdC


 


1746
Q92838|EDA_HUMAN
328
332
PFlqC


 


1747
Q92995|UBP13_HUMAN
540
544
PFsaC


 


1748
Q93008|USP9X_HUMAN
251
255
PFgqC


 


1749
Q96F10|SAT2_HUMAN
50
54
PFyhC


 


1750
Q96FV3|TSN17_HUMAN
185
189
PFscC


 


1751
Q96IK0|TM101_HUMAN
27
31
PFwgC


 


1752
Q96L50|LLR1_HUMAN
344
348
PFhlC


 


1753
Q96L73|NSD1_HUMAN
456
460
PFedC


 


1754
Q96P88|GNRR2_HUMAN
184
188
PFtqC


 


1755
Q96PZ7|CSMD1_HUMAN
2139
2143
PFprC


 


1756
Q96R06|SPAG5_HUMAN
378
382
PFstC


 


1757
Q96RG2|PASK_HUMAN
542
546
PFasC


 


1758
Q96RJ0|TAAR1_HUMAN
266
270
PFfiC


 


1759
Q96RQ9|OXLA_HUMAN
32
36
PFekC


 


1760
Q96SE7|ZN347_HUMAN
798
802
PFsiC


 


1761
Q96T25|ZIC5_HUMAN
470
474
PFpgC


 


1762
Q99666|RGPD8_HUMAN
517
521
PFpvC


 


1763
Q99698|LYST_HUMAN
254
258
PFdlC


 


1764
Q99726|ZNT3_HUMAN
51
55
PFhhC


 


1765
Q9BSE5|SPEB_HUMAN
204
208
PFrrC


 


1766
Q9BWQ6|YIPF2_HUMAN
124
128
PFwiC


 


1767
Q9BXC9|BBS2_HUMAN
530
534
PFqvC


 


1768
Q9BXJ4|C1QT3_HUMAN
18
22
PFclC


 


1769
Q9BXK1|KLF16_HUMAN
130
134
PFpdC


 


1770
Q9BZE2|PUS3_HUMAN
261
265
PFqlC


 


1771
Q9C0C4|SEM4C_HUMAN
719
723
PFrpC


 


1772
Q9C0E2|XPO4_HUMAN
50
54
PFavC


 


1773
Q9C0I4|THS7B_HUMAN
1482
1486
PFsyC


 


1774
Q9GZN6|S6A16_HUMAN
271
275
PFflC


 


1775
Q9GZU2|PEG3_HUMAN
1330
1334
PFyeC


 


1776
Q9GZZ0|HXD1_HUMAN
162
166
PFpaC


 


1777
Q9H0A6|RNF32_HUMAN
344
348
PFhaC


 


1778
Q9H0B3|K1683_HUMAN
326
330
PFqiC


 


1779
Q9H267|VP33B_HUMAN
189
193
PFpnC


 


1780
Q9H2J1|CI037_HUMAN
102
106
PFekC


 


1781
Q9H3H5|GPT_HUMAN
77
81
PFlnC


 


1782
Q9H8V3|ECT2_HUMAN
239
243
PFqdC


 


1783
Q9H9S0|NANOG_HUMAN
239
243
PFynC


 


1784
Q9H9V4|RN122_HUMAN
3
7
PFqwC


 


1785
Q9HAQ2|KIF9_HUMAN
291
295
PFrqC


 


1786
Q9HAW7|UD17_HUMAN
149
153
PFdaC


 


1787
Q9HAW8|UD110_HUMAN
149
153
PFdtC


 


1788
Q9HAW9|UD18_HUMAN
149
153
PFdaC


 


1789
Q9HBX8|LGR6_HUMAN
412
416
PFkpC


 


1790
Q9NQW8|CNGB3_HUMAN
309
313
PFdiC


 


1791
Q9NRZ9|HELLS_HUMAN
273
277
PFlvC


 


1792
Q9NTG7|SIRT3_HUMAN
30
34
PFqaC


 


1793
Q9NWZ5|UCKL1_HUMAN
370
374
PFqdC


 


1794
Q9NY30|BTG4_HUMAN
98
102
PFevC


 


1795
Q9NYM4|GPR83_HUMAN
342
346
PFiyC


 


1796
Q9NYV6|RRN3_HUMAN
561
565
PFdpC


 


1797
Q9NYW1|TA2R9_HUMAN
190
194
PFilC


 


1798
Q9NYW3|TA2R7_HUMAN
193
197
PFcvC


 


1799
Q9NZ56|FMN2_HUMAN
716
720
PFsdC


 


1800
Q9NZ71|RTEL1_HUMAN
495
499
PFpvC


 


1801
Q9NZD2|GLTP_HUMAN
31
35
PFfdC


 


1802
Q9P2N4|ATS9_HUMAN
596
600
PFgtC


 


1803
Q9UBR1|BUP1_HUMAN
124
128
PFafC


 


1804
Q9UBS0|KS6B2_HUMAN
344
348
PFrpC


 


1805
Q9UET6|RRMJ1_HUMAN
234
238
PFvtC


 


1806
Q9UHD4|CIDEB_HUMAN
37
41
PFrvC


 


1807
Q9UKA4|AKA11_HUMAN
917
921
PFshC


 


1808
Q9ULC3|RAB23_HUMAN
230
234
PFssC


 


1809
Q9ULJ3|ZN295_HUMAN
125
129
PFptC


 


1810
Q9ULK4|CRSP3_HUMAN
1086
1090
PFpnC


 


1811
Q9ULL4|PLXB3_HUMAN
24
28
PFglC


 


1812
Q9ULV8|CBLC_HUMAN
387
391
PFcrC


 


1813
Q9UM47|NOTC3_HUMAN
1357
1361
PFfrC


 


1814
Q9UNQ2|DIMT1_HUMAN
146
150
PFfrC


 


1815
Q9Y3D5|RT18C_HUMAN
86
90
PFtgC


 


1816
Q9Y3F1|TA6P_HUMAN
25
29
PFpsC


 


1817
Q9Y3R5|CU005_HUMAN
255
259
PFytC


 


1818
Q9Y450|HBS1L_HUMAN
487
491
PFrlC


 


1819
Q9Y493|ZAN_HUMAN
1364
1368
PFetC


 


1820
Q9Y493|ZAN_HUMAN
1751
1755
PFsqC


 


1821
Q9Y493|ZAN_HUMAN
2556
2560
PFaaC


 


1822
Q9Y548|YIPF1_HUMAN
123
127
PFwiC


 


1823
Q9Y5L3|ENP2_HUMAN
324
328
PFsrC


 


1824
Q9Y5P8|2ACC_HUMAN
272
276
PFqdC


 


1825
Q9Y664|KPTN_HUMAN
143
147
PFqlC


 


1826
Q9Y678|COPG_HUMAN
226
230
PFayC


 


1827
Q9Y6E0|STK24_HUMAN
371
375
PFsqC


 


1828
Q9Y6R7|FCGBP_HUMAN
683
687
PFavC


 


1829
Q9Y6R7|FCGBP_HUMAN
1074
1078
PFreC


 


1830
Q9Y6R7|FCGBP_HUMAN
1888
1892
PFttC


 


1831
Q9Y6R7|FCGBP_HUMAN
3089
3093
PFttC


 


1832
Q9Y6R7|FCGBP_HUMAN
4290
4294
PFttC


 


1833
Q9Y6R7|FCGBP_HUMAN
5059
5063
PFatC
















TABLE 7A







Table of the amino acid sequences of the peptides


predicted similar to Growth Hormone












Peptide



Protein Name
Peptide Location
sequence
SEQ ID NO:





Placental Lactogen
AAA98621(101-114)
LLRISLLLIESWLE
2483


 


hGH-V
AAB59548(101-114)
LLRISLLLTQSWLE
2490


 


GH2
CAG46722(101-114)
LLHISLLLIQSWLE
2491


 


Chorionic
AAA52116(101-113)
LLRLLLLIESWLE
2480


somatomammotropin





 


Chorionic
AAI19748(12-25)
LLHISLLLIESRLE
2482


somatomammotropin





hormone-like 1





 


Transmembrane
NP_060474(181-194)
LLRSSLILLQGSWF
2481


protein 45A





 


IL-17 receptor C
Q8NAC3(376-387)
RLRLLTLQSWLL
2477


 


Neuropeptide
Q9Y5X5(378-390)
LLIVALLFILSWL
2479


FF receptor 2





 


Brush border
AAC27437(719-731)
LMRKSQILISSWF
2478


myosin-I
















TABLE 7B







Table of the amino acid sequences of the peptides


predicted similar to PEDF.












Peptide



Protein Name
Peptide Location
sequence
SEQ ID NO:





DEAH box polypeptide
AAH47327(438-448)
EIELVEEEPPF
2485


8 (“DEAH” disclosed





as SEQ ID NO: 2484)





 


Caspase 10
CAD32371(67-77)
AEDLLSEEDPF
2492


 


CKIP-1
CAI14263(66-76)
TLDLIQEEDPS
2493
















TABLE 8







Amino acid sequences of peptides that contain the


somatotropin motif.


Somatotropins


Motif: L-X(3)-L-L-X(3)-S-X-L


Number of Locations: 139


Number of Different Proteins: 139











SEQ






ID
Accession





 NO:
Number|Protein Name
First Amino acid
Last Amino acid
Sequence














1834
O14569|C56D2_HUMAN
164
175
LvgyLLgsaSlL


 


1835
O15287|FANCG_HUMAN
416
427
LceeLLsrtSsL


 


1836
O15482|TEX28_HUMAN
338
349
LatvLLvfvStL


 


1837
O43914|TYOBP_HUMAN
11
22
LllpLLlavSgL


 


1838
O60609|GFRA3_HUMAN
15
26
LmllLLlppSpL


 


1839
O75844|FACE1_HUMAN
279
290
LfdtLLeeySvL


 


1840
O95747|OXSR1_HUMAN
90
101
LvmkLLsggSvL


 


1841
P01241|SOMA_HUMAN
102
113
LrisLLliqSwL


 


1842
P01242|SOM2_HUMAN
102
113
LrisLLliqSwL


 


1843
P01243|CSH_HUMAN
102
113
LrisLLlieSwL


 


1844
P02750|A2GL_HUMAN
83
94
LpanLLqgaSkL


 


1845
P03891|NU2M_HUMAN
149
160
LnvsLLltlSiL


 


1846
P04201|MAS_HUMAN
151
162
LvcaLLwalScL


 


1847
P05783|K1C18_HUMAN
338
349
LngiLLhleSeL


 


1848
P07359|GP1BA_HUMAN
3
14
LlllLLllpSpL


 


1849
P09848|LPH_HUMAN
35
46
LtndLLhnlSgL


 


1850
P11168|GTR2_HUMAN
136
147
LvgaLLmgfSkL


 


1851
P12034|FGF5_HUMAN
3
14
LsflLLlffShL


 


1852
P13489|RINI_HUMAN
247
258
LcpgLLhpsSrL


 


1853
P14902|I23O_HUMAN
196
207
LlkaLLeiaScL


 


1854
P16278|BGAL_HUMAN
135
146
LpawLLekeSiL


 


1855
P19838|NFKB1_HUMAN
558
569
LvrdLLevtSgL


 


1856
P22079|PERL_HUMAN
512
523
LvrgLLakkSkL


 


1857
P23276|KELL_HUMAN
53
64
LilgLLlcfSvL


 


1858
P24394|IL4RA_HUMAN
4
15
LcsgLLfpvScL


 


1859
P29320|EPHA3_HUMAN
5
16
LsilLLlscSvL


 


1860
P31512|FMO4_HUMAN
524
535
LaslLLickSsL


 


1861
P35270|SPRE_HUMAN
26
37
LlasLLspgSvL


 


1862
P41250|SYG_HUMAN
20
31
LpprLLarpSlL


 


1863
P42575|CASP2_HUMAN
114
125
LedmLLttlSgL


 


1864
P46721|SO1A2_HUMAN
396
407
LleyLLyflSfL


 


1865
P51665|PSD7_HUMAN
201
212
LnskLLdirSyL


 


1866
P59531|T2R12_HUMAN
188
199
LisfLLsliSlL


 


1867
P69849|NOMO3_HUMAN
1180
1191
LiplLLqltSrL


 


1868
P98161|PKD1_HUMAN
82
93
LdvgLLanlSaL


 


1869
P98171|RHG04_HUMAN
153
164
LqdeLLevvSeL


 


1870
P98196|AT11A_HUMAN
1077
1088
LaivLLvtiSlL


 


1871
Q08431|MFGM_HUMAN
10
21
LcgaLLcapSlL


 


1872
Q08AF3|SLFN5_HUMAN
533
544
LvivLLgfkSfL


 


1873
Q12952|FOXL1_HUMAN
293
304
LgasLLaasSsL


 


1874
Q13275|SEM3F_HUMAN
2
13
LvagLLlwaSlL


 


1875
Q13394|MB211_HUMAN
300
311
LngiLLqliScL


 


1876
Q13609|DNSL3_HUMAN
8
19
LlllLLsihSaL


 


1877
Q13619|CUL4A_HUMAN
213
224
LlrsLLgmlSdL


 


1878
Q13620|CUL4B_HUMAN
349
360
LlrsLLsmlSdL


 


1879
Q14406|CSHL_HUMAN
84
95
LhisLLlieSrL


 


1880
Q14667|K0100_HUMAN
8
19
LlvlLLvalSaL


 


1881
Q15155|NOMO1_HUMAN
1180
1191
LiplLLqltSrL


 


1882
Q15760|GPR19_HUMAN
279
290
LilnLLfllSwL


 


1883
Q53RE8|ANR39_HUMAN
166
177
LacdLLpcnSdL


 


1884
Q5FWE3|PRRT3_HUMAN
586
597
LatdLLstwSvL


 


1885
Q5GH73|XKR6_HUMAN
630
641
LlyeLLqyeSsL


 


1886
Q5GH77|XKR3_HUMAN
194
205
LnraLLmtfSlL


 


1887
Q5JPE7|NOMO2_HUMAN
1180
1191
LiplLLqltSrL


 


1888
Q5JWR5|DOP1_HUMAN
506
517
LpqlLLrmiSaL


 


1889
Q5UIP0|RIF1_HUMAN
2413
2424
LsknLLaqiSaL


 


1890
Q5VTE6|ANGE2_HUMAN
175
186
LsqdLLednShL


 


1891
Q5VU43|MYOME_HUMAN
1932
1943
LreaLLssrShL


 


1892
Q5VYK3|ECM29_HUMAN
1296
1307
LipaLLeslSvL


 


1893
Q68D06|SLN13_HUMAN
554
565
LvivLLgfrSlL


 


1894
Q6GYQ0|GRIPE_HUMAN
641
652
LwddLLsvlSsL


 


1895
Q6NTF9|RHBD2_HUMAN
166
177
LvpwLLlgaSwL


 


1896
Q6ZMH5|S39A5_HUMAN
217
228
LavlLLslpSpL


 


1897
Q6ZMZ3|SYNE3_HUMAN
532
543
LhnsLLqrkSkL


 


1898
Q6ZVD8|PHLPL_HUMAN
313
324
LfpiLLceiStL


 


1899
Q6ZVE7|GOT1A_HUMAN
23
34
LfgtLLyfdSvL


 


1900
Q70J99|UN13D_HUMAN
927
938
LrveLLsasSlL


 


1901
Q7Z3Z4|PIWL4_HUMAN
139
150
LriaLLyshSeL


 


1902
Q7Z6Z7|HUWE1_HUMAN
841
852
LqegLLqldSiL


 


1903
Q7Z7L1|SLN11_HUMAN
554
565
LvivLLgfrSlL


 


1904
Q86SM5|MRGRG_HUMAN
223
234
LlnfLLpvfSpL


 


1905
Q86U44|MTA70_HUMAN
78
89
LekkLLhhlSdL


 


1906
Q86UQ4|ABCAD_HUMAN
3182
3193
LlnsLLdivSsL


 


1907
Q86WI3|NLRC5_HUMAN
1485
1496
LlqsLLlslSeL


 


1908
Q86YC3|LRC33_HUMAN
263
274
LffpLLpqySkL


 


1909
Q8IYK4|GT252_HUMAN
9
20
LawsLLllsSaL


 


1910
Q8IYS0|GRM1C_HUMAN
485
496
LesdLLieeSvL


 


1911
Q8IZL8|PELP1_HUMAN
33
44
LrllLLesvSgL


 


1912
Q8IZY2|ABCA7_HUMAN
1746
1757
LftlLLqhrSqL


 


1913
Q8N0X7|SPG20_HUMAN
322
333
LfedLLrqmSdL


 


1914
Q8N6M3|CT142_HUMAN
33
44
LagsLLkelSpL


 


1915
Q8N816|TMM99_HUMAN
96
107
LlpcLLgvgSwL


 


1916
Q8NBM4|PDHL1_HUMAN
15
26
LsksLLlvpSaL


 


1917
Q8NCG7|DGLB_HUMAN
555
566
LtqpLLgeqSlL


 


1918
Q8NFR9|I17RE_HUMAN
80
91
LcqhLLsggSgL


 


1919
Q8NGE3|O10P1_HUMAN
9
20
LpefLLlgfSdL


 


1920
Q8TCV5|WFDC5_HUMAN
8
19
LlgaLLavgSqL


 


1921
Q8TDL5|LPLC1_HUMAN
165
176
LriqLLhklSfL


 


1922
Q8TE82|S3TC1_HUMAN
1025
1036
LegqLLetiSqL


 


1923
Q8TEQ8|PIGO_HUMAN
857
868
LvflLLflqSfL


 


1924
Q8TEZ7|MPRB_HUMAN
127
138
LlahLLqskSeL


 


1925
Q8WWN8|CEND3_HUMAN
1481
1492
LeeqLLqelSsL


 


1926
Q8WZ84|OR8D1_HUMAN
43
54
LgmiLLiavSpL


 


1927
Q92535|PIGC_HUMAN
253
264
LfalLLmsiScL


 


1928
Q92538|GBF1_HUMAN
1224
1235
LrilLLmkpSvL


 


1929
Q92743|HTRA1_HUMAN
262
273
LpvlLLgrsSeL


 


1930
Q92935|EXTL1_HUMAN
19
30
LllvLLggfSlL


 


1931
Q93074|MED12_HUMAN
401
412
LqtiLLccpSaL


 


1932
Q96DN6|MBD6_HUMAN
740
751
LgasLLgdlSsL


 


1933
Q96GR4|ZDH12_HUMAN
48
59
LtflLLvlgSlL


 


1934
Q96HP8|T176A_HUMAN
29
40
LaklLLtccSaL


 


1935
Q96K12|FACR2_HUMAN
380
391
LmnrLLrtvSmL


 


1936
Q96KP1|EXOC2_HUMAN
339
350
LldkLLetpStL


 


1937
Q96MX0|CKLF3_HUMAN
40
51
LkgrLLlaeSgL


 


1938
Q96Q45|AL2S4_HUMAN
387
398
LvvaLLvglSwL


 


1939
Q96QZ0|PANX3_HUMAN
136
147
LssdLLfiiSeL


 


1940
Q96RQ9|OXLA_HUMAN
269
280
LpraLLsslSgL


 


1941
Q9BY08|EBPL_HUMAN
178
189
LipgLLlwqSwL


 


1942
Q9BZ97|TTY13_HUMAN
30
41
LclmLLlagScL


 


1943
Q9H1Y0|ATG5_HUMAN
85
96
LlfdLLassSaL


 


1944
Q9H254|SPTN4_HUMAN
1422
1433
LdkkLLhmeSqL


 


1945
Q9H330|CI005_HUMAN
430
441
LgkfLLkvdSkL


 


1946
Q9H4I8|SEHL2_HUMAN
175
186
LlqrLLksnShL


 


1947
Q9HCN3|TMEM8_HUMAN
200
211
LpqtLLshpSyL


 


1948
Q9NQ34|TMM9B_HUMAN
4
15
LwggLLrlgSlL


 


1949
Q9NR09|BIRC6_HUMAN
1400
1411
LlkaLLdnmSfL


 


1950
Q9NRA0|SPHK2_HUMAN
296
307
LgldLLlncSlL


 


1951
Q9NRU3|CNNM1_HUMAN
156
167
LgalLLlalSaL


 


1952
Q9NTT1|U2D3L_HUMAN
99
110
LskvLLsicSlL


 


1953
Q9NVH2|INT7_HUMAN
623
634
LridLLqafSqL


 


1954
Q9NVM9|CL011_HUMAN
350
361
LtnfLLngrSvL


 


1955
Q9NZD1|GPC5D_HUMAN
60
71
LptqLLfllSvL


 


1956
Q9P2E9|RRBP1_HUMAN
1226
1237
LrqlLLesqSqL


 


1957
Q9P2G4|K1383_HUMAN
397
408
LlnaLLvelSlL


 


1958
Q9P2V4|LRIT1_HUMAN
541
552
LpltLLvccSaL


 


1959
Q9UDY8|MALT1_HUMAN
33
44
LrepLLrrlSeL


 


1960
Q9UEW8|STK39_HUMAN
138
149
LvmkLLsggSmL


 


1961
Q9UGN4|CM35H_HUMAN
188
199
LlllLLvgaSlL


 


1962
Q9UHD4|CIDEB_HUMAN
189
200
LghmLLgisStL


 


1963
Q9UIG8|SO3A1_HUMAN
270
281
LcgaLLffsSlL


 


1964
Q9UPA5|BSN_HUMAN
353
364
LgasLLtqaStL


 


1965
Q9UPX8|SHAN2_HUMAN
609
620
LtgrLLdpsSpL


 


1966
Q9Y239|NOD1_HUMAN
318
329
LsgkLLkgaSkL


 


1967
Q9Y2I2|NTNG1_HUMAN
526
537
LlttLLgtaSpL


 


1968
Q9Y2U2|KCNK7_HUMAN
92
103
LpsaLLfaaSiL


 


1969
Q9Y2Y8|PRG3_HUMAN
7
18
LpflLLgtvSaL


 


1970
Q9Y586|MB212_HUMAN
300
311
LngiLLqliScL


 


1971
Q9Y5X0|SNX10_HUMAN
106
117
LqnaLLlsdSsL


 


1972
Q9Y5X5|NPFF2_HUMAN
379
390
LivaLLfilSwL
















TABLE 9







Table of the amino acid sequences of the peptides


identified to contain the serpin motif.


Serpins


Motif: L-X(2)-E-E-X-P


Number of Locations: 314


Number of Different Proteins: 302











SEQ

First
Last



ID
Accession
Amino
Amino 



NO:
Number|Protein Name
acid
acid
Sequence














1973
O00160|MYO1F_HUMAN
744
751
LglEErPe


 


1974
O00507|USP9Y_HUMAN
2474
2481
LcpEEePd


 


1975
O00625|PIR_HUMAN
134
141
LksEEiPk


 


1976
O14641|DVL2_HUMAN
20
27
LdeEEtPy


 


1977
O14686|MLL2_HUMAN
2819
2826
LgpEErPp


 


1978
O14709|ZN197_HUMAN
193
200
LsqEEnPr


 


1979
O14795|UN13B_HUMAN
1499
1506
LgnEEgPe


 


1980
O15013|ARHGA_HUMAN
199
206
LssEEpPt


 


1981
O15055|PER2_HUMAN
994
1001
LqlEEaPe


 


1982
O15528|CP27B_HUMAN
297
304
LfrEElPa


 


1983
O15534|PER1_HUMAN
987
994
LqlEElPr


 


1984
O43390|HNRPR_HUMAN
12
19
LkeEEePm


 


1985
O60216|RAD21_HUMAN
504
511
LppEEpPn


 


1986
O60237|MYPT2_HUMAN
339
346
LyeEEtPk


 


1987
O60346|PHLPP_HUMAN
483
490
LeaEEkPl


 


1988
O60779|S19A2_HUMAN
259
266
LnmEEpPv


 


1989
O60885|BRD4_HUMAN
913
920
LedEEpPa


 


1990
O75128|COBL_HUMAN
1064
1071
LerEEkPs


 


1991
O75420|PERQ1_HUMAN
334
341
LeeEEePs


 


1992
O75787|RENR_HUMAN
116
123
LfsEEtPv


 


1993
O75914|PAK3_HUMAN
5
12
LdnEEkPp


 


1994
O94933|SLIK3_HUMAN
227
234
LqlEEnPw


 


1995
O94966|UBP19_HUMAN
1251
1258
LeaEEePv


 


1996
O94986|CE152_HUMAN
847
854
LknEEvPv


 


1997
O94991|SLIK5_HUMAN
230
237
LqlEEnPw


 


1998
O95153|RIMB1_HUMAN
915
922
LngEEcPp


 


1999
O95279|KCNK5_HUMAN
443
450
LagEEsPq


 


2000
O95712|PA24B_HUMAN
772
779
LkiEEpPs


 


2001
O95881|TXD12_HUMAN
94
101
LedEEePk


 


2002
O96018|APBA3_HUMAN
116
123
LhcEEcPp


 


2003
O96024|B3GT4_HUMAN
217
224
LhsEEvPl


 


2004
P04275|VWF_HUMAN
1012
1019
LqvEEdPv


 


2005
P05160|F13B_HUMAN
18
25
LyaEEkPc


 


2006
P06858|LIPL_HUMAN
279
286
LlnEEnPs


 


2007
P07237|PDIA1_HUMAN
307
314
LkkEEcPa


 


2008
P07949|RET_HUMAN
1033
1040
LseEEtPl


 


2009
P08519|APOA_HUMAN
3880
3887
LpsEEaPt


 


2010
P09769|FGR_HUMAN
497
504
LdpEErPt


 


2011
P10745|IRBP_HUMAN
708
715
LvvEEaPp


 


2012
P11532|DMD_HUMAN
2255
2262
LlvEElPl


 


2013
P14317|HCLS1_HUMAN
352
359
LqvEEePv


 


2014
P16150|LEUK_HUMAN
369
376
LkgEEePl


 


2015
P17025|ZN182_HUMAN
79
86
LevEEcPa


 


2016
P17600|SYN1_HUMAN
239
246
LgtEEfPl


 


2017
P18583|SON_HUMAN
1149
1156
LppEEpPt


 


2018
P18583|SON_HUMAN
1160
1167
LppEEpPm


 


2019
P18583|SON_HUMAN
1171
1178
LppEEpPe


 


2020
P19484|TFEB_HUMAN
350
357
LpsEEgPg


 


2021
P21333|FLNA_HUMAN
1034
1041
LprEEgPy


 


2022
P21802|FGFR2_HUMAN
33
40
LepEEpPt


 


2023
P22001|KCNA3_HUMAN
152
159
LreEErPl


 


2024
P31629|ZEP2_HUMAN
772
779
LvsEEsPs


 


2025
P34925|RYK_HUMAN
578
585
LdpEErPk


 


2026
P36955|PEDF_HUMAN
39
46
LveEEdPf


 


2027
P40189|IL6RB_HUMAN
787
794
LdsEErPe


 


2028
P42898|MTHR_HUMAN
598
605
LyeEEsPs


 


2029
P48729|KC1A_HUMAN
266
273
LrfEEaPd


 


2030
P51512|MMP16_HUMAN
165
172
LtfEEvPy


 


2031
P52746|ZN142_HUMAN
750
757
LgaEEnPl


 


2032
P53370|NUDT6_HUMAN
284
291
LtvEElPa


 


2033
P53801|PTTG_HUMAN
167
174
LfkEEnPy


 


2034
P53804|TTC3_HUMAN
2001
2008
LltEEsPs


 


2035
P55285|CADH6_HUMAN
116
123
LdrEEkPv


 


2036
P55289|CAD12_HUMAN
117
124
LdrEEkPf


 


2037
P56645|PER3_HUMAN
929
936
LlqEEmPr


 


2038
P59797|SELV_HUMAN
163
170
LlpEEdPe


 


2039
Q01826|SATB1_HUMAN
409
416
LrkEEdPk


 


2040
Q04725|TLE2_HUMAN
200
207
LveEErPs


 


2041
Q06330|SUH_HUMAN
7
14
LpaEEpPa


 


2042
Q06889|EGR3_HUMAN
24
31
LypEEiPs


 


2043
Q07157|ZO1_HUMAN
1155
1162
LrhEEqPa


 


2044
Q13072|BAGE1_HUMAN
19
26
LmkEEsPv


 


2045
Q13087|PDIA2_HUMAN
497
504
LptEEpPe


 


2046
Q13255|GRM1_HUMAN
995
1002
LtaEEtPl


 


2047
Q13315|ATM_HUMAN
954
961
LpgEEyPl


 


2048
Q13439|GOGA4_HUMAN
2092
2099
LeqEEnPg


 


2049
Q13596|SNX1_HUMAN
265
272
LekEElPr


 


2050
Q13634|CAD18_HUMAN
446
453
LdrEEtPw


 


2051
Q14028|CNGB1_HUMAN
137
144
LmaEEnPp


 


2052
Q14126|DSG2_HUMAN
117
124
LdrEEtPf


 


2053
Q14204|DYHC_HUMAN
3973
3980
LwsEEtPa


 


2054
Q14315|FLNC_HUMAN
1738
1745
LphEEePs


 


2055
Q14524|SCN5A_HUMAN
46
53
LpeEEaPr


 


2056
Q14554|PDIA5_HUMAN
166
173
LkkEEkPl


 


2057
Q14562|DHX8_HUMAN
411
418
LskEEfPd


 


2058
Q14562|DHX8_HUMAN
441
448
LveEEpPf


 


2059
Q14573|ITPR3_HUMAN
315
322
LaaEEnPs


 


2060
Q14674|ESPL1_HUMAN
613
620
LspEEtPa


 


2061
Q14676|MDC1_HUMAN
145
152
LtvEEtPr


 


2062
Q14684|RRP1B_HUMAN
244
251
LsaEEiPe


 


2063
Q15021|CND1_HUMAN
1179
1186
LgvEEePf


 


2064
Q15735|PI5PA_HUMAN
189
196
LasEEqPp


 


2065
Q15788|NCOA1_HUMAN
982
989
LimEErPn


 


2066
Q15878|CAC1E_HUMAN
797
804
LnrEEaPt


 


2067
Q2TAL6|VWC2_HUMAN
179
186
LctEEgPl


 


2068
Q32MZ4|LRRF1_HUMAN
82
89
LrvEErPe


 


2069
Q32P28|P3H1_HUMAN
215
222
LysEEqPq


 


2070
Q3KNS1|PTHD3_HUMAN
96
103
LpeEEtPe


 


2071
Q3ZCX4|ZN568_HUMAN
100
107
LeqEEePw


 


2072
Q495W5|FUT11_HUMAN
144
151
LlhEEsPl


 


2073
Q52LD8|RFTN2_HUMAN
123
130
LviEEcPl


 


2074
Q53GL0|PKHO1_HUMAN
189
196
LiqEEdPs


 


2075
Q53GL0|PKHO1_HUMAN
289
296
LraEEpPt


 


2076
Q53GL7|PAR10_HUMAN
693
700
LeaEEpPd


 


2077
Q53H47|SETMR_HUMAN
499
506
LdqEEaPk


 


2078
Q567U6|CCD93_HUMAN
300
307
LsaEEsPe


 


2079
Q580R0|CB027_HUMAN
41
48
LelEEaPe


 


2080
Q587I9|SFT2C_HUMAN
136
143
LrcEEaPs


 


2081
Q5H9T9|CN155_HUMAN
427
434
LlpEEaPr


 


2082
Q5H9T9|CN155_HUMAN
697
704
LpaEEtPi


 


2083
Q5H9T9|CN155_HUMAN
736
743
LltEEfPi


 


2084
Q5JUK9|GGED1_HUMAN
38
45
LqqEEpPi


 


2085
Q5JXB2|UE2NL_HUMAN
58
65
LlaEEyPm


 


2086
Q5MCW4|ZN569_HUMAN
60
67
LeqEEePw


 


2087
Q5SYB0|FRPD1_HUMAN
553
560
LikEEqPp


 


2088
Q5THJ4|VP13D_HUMAN
2943
2950
LtgEEiPf


 


2089
Q5VYS4|CM033_HUMAN
293
300
LesEEtPn


 


2090
Q5VZP5|DUS27_HUMAN
942
949
LrtEEkPp


 


2091
Q5VZY2|PPC1A_HUMAN
247
254
LkkEErPt


 


2092
Q63HR2|TENC1_HUMAN
564
571
LddEEqPt


 


2093
Q66K74|MAP1S_HUMAN
777
784
LgaEEtPp


 


2094
Q68CZ1|FTM_HUMAN
1181
1188
LpaEEtPv


 


2095
Q68DD2|PA24F_HUMAN
470
477
LyqEEnPa


 


2096
Q6BDS2|URFB1_HUMAN
1304
1311
LedEEiPv


 


2097
Q6DCA0|AMERL_HUMAN
183
190
LtrEElPk


 


2098
Q6DN90|IQEC1_HUMAN
263
270
LhtEEaPa


 


2099
Q6DT37|MRCKG_HUMAN
1264
1271
LvpEElPp


 


2100
Q6HA08|ASTL_HUMAN
62
69
LilEEtPe


 


2101
Q6IFS5|HSN2_HUMAN
298
305
LnqEElPp


 


2102
Q6NUN7|CK063_HUMAN
74
81
LdeEEsPr


 


2103
Q6P2Q9|PRP8_HUMAN
1852
1859
LpvEEqPk


 


2104
Q6P5W5|S39A4_HUMAN
473
480
LvaEEsPe


 


2105
Q6P6B1|CH047_HUMAN
249
256
LgkEEqPq


 


2106
Q6PD74|P34_HUMAN
141
148
LspEElPe


 


2107
Q6PI48|SYDM_HUMAN
488
495
LpkEEnPr


 


2108
Q6PJ61|FBX46_HUMAN
246
253
LrkEErPg


 


2109
Q6S8J7|POTE8_HUMAN
307
314
LtsEEePq


 


2110
Q6SZW1|SARM1_HUMAN
396
403
LlgEEvPr


 


2111
Q6UX39|AMTN_HUMAN
114
121
LssEElPq


 


2112
Q6ZMY3|SPOC1_HUMAN
184
191
LskEEpPg


 


2113
Q6ZN11|ZN793_HUMAN
60
67
LeqEEaPw


 


2114
Q6ZNL6|FGD5_HUMAN
382
389
LraEEnPm


 


2115
Q6ZV29|PLPL7_HUMAN
854
861
LhrEEgPa


 


2116
Q70CQ4|UBP31_HUMAN
527
534
LpqEEqPl


 


2117
Q70SY1|CR3L2_HUMAN
153
160
LekEEpPl


 


2118
Q7L8C5|SYT13_HUMAN
229
236
LaeEElPt


 


2119
Q7Z3E5|ARMC9_HUMAN
570
577
LnsEElPd


 


2120
Q7Z410|TMPS9_HUMAN
691
698
LacEEaPg


 


2121
Q86SP6|GP149_HUMAN
217
224
LcsEEpPr


 


2122
Q86V87|RAI16_HUMAN
496
503
LdlEEdPy


 


2123
Q86VQ0|CF152_HUMAN
428
435
LerEEkPe


 


2124
Q86W50|MET10_HUMAN
454
461
LsqEEnPe


 


2125
Q86Y13|DZIP3_HUMAN
1192
1199
LlpEEfPg


 


2126
Q86Y27|BAGE5_HUMAN
19
26
LmkEEsPv


 


2127
Q86Y28|BAGE4_HUMAN
19
26
LmkEEsPv


 


2128
Q86Y29|BAGE3_HUMAN
19
26
LmkEEsPv


 


2129
Q86Y30|BAGE2_HUMAN
19
26
LmkEEsPv


 


2130
Q8IU99|FA26C_HUMAN
315
322
LgqEEpPl


 


2131
Q8IUA0|WFDC8_HUMAN
217
224
LqdEEcPl


 


2132
Q8IV63|VRK3_HUMAN
438
445
LtyEEkPp


 


2133
Q8IWY9|CDAN1_HUMAN
948
955
LlpEEtPa


 


2134
Q8IXI1|MIRO2_HUMAN
24
31
LvgEEfPe


 


2135
Q8IXI2|MIRO1_HUMAN
24
31
LvsEEfPe


 


2136
Q8IYS5|OSCAR_HUMAN
122
129
LvtEElPr


 


2137
Q8IZ26|ZNF34_HUMAN
251
258
LhtEEkPy


 


2138
Q8IZH2|XRN1_HUMAN
1143
1150
LfdEEfPg


 


2139
Q8IZP0|ABI1_HUMAN
7
14
LleEEiPs


 


2140
Q8N201|INT1_HUMAN
1587
1594
LlqEEePl


 


2141
Q8N309|LRC43_HUMAN
373
380
LlvEEsPe


 


2142
Q8N3C0|HELC1_HUMAN
451
458
LsfEEkPv


 


2143
Q8N3C0|HELC1_HUMAN
1579
1586
LatEEdPk


 


2144
Q8N475|FSTL5_HUMAN
786
793
LkaEEwPw


 


2145
Q8N4L2|TM55A_HUMAN
132
139
LisEEqPa


 


2146
Q8N752|KC1AL_HUMAN
266
273
LrfEEvPd


 


2147
Q8NC74|CT151_HUMAN
178
185
LrgEEkPa


 


2148
Q8NE71|ABCF1_HUMAN
701
708
LrmEEtPt


 


2149
Q8NEG5|ZSWM2_HUMAN
43
50
LlrEEePe


 


2150
Q8NEM7|FA48A_HUMAN
115
122
LdaEElPp


 


2151
Q8NEZ4|MLL3_HUMAN
3046
3053
LllEEqPl


 


2152
Q8NEZ4|MLL3_HUMAN
4023
4030
LvkEEpPe


 


2153
Q8NFM7|I17RD_HUMAN
702
709
LgeEEpPa


 


2154
Q8NFP4|MDGA1_HUMAN
489
496
LplEEtPd


 


2155
Q8NHJ6|LIRB4_HUMAN
60
67
LdkEEsPa


 


2156
Q8NI51|BORIS_HUMAN
120
127
LwlEEgPr


 


2157
Q8TBH0|ARRD2_HUMAN
387
394
LysEEdPn


 


2158
Q8TDX9|PK1L1_HUMAN
1101
1108
LsaEEsPg


 


2159
Q8TE68|ES8L1_HUMAN
408
415
LspEEgPp


 


2160
Q8TER0|SNED1_HUMAN
1083
1090
LrgEEhPt


 


2161
Q8WU49|CG033_HUMAN
8
15
LslEEcPw


 


2162
Q8WUA2|PPIL4_HUMAN
16
23
LytEErPr


 


2163
Q8WUI4|HDAC7_HUMAN
943
950
LveEEePm


 


2164
Q8WWN8|CEND3_HUMAN
1456
1463
LgqEErPp


 


2165
Q8WZ42|TITIN_HUMAN
12132
12139
LvvEElPv


 


2166
Q8WZ42|TITIN_HUMAN
13832
13839
LfvEEiPv


 


2167
Q92538|GBF1_HUMAN
1062
1069
LqrEEtPs


 


2168
Q92738|US6NL_HUMAN
51
58
LheEElPd


 


2169
Q92765|SFRP3_HUMAN
134
141
LacEElPv


 


2170
Q92851|CASPA_HUMAN
70
77
LlsEEdPf


 


2171
Q92888|ARHG1_HUMAN
390
397
LepEEpPg


 


2172
Q93008|USP9X_HUMAN
2466
2473
LcpEEePd


 


2173
Q969V6|MKL1_HUMAN
497
504
LvkEEgPr


 


2174
Q96B01|R51A1_HUMAN
55
62
LrkEEiPv


 


2175
Q96D15|RCN3_HUMAN
192
199
LhpEEfPh


 


2176
Q96DC7|TMCO6_HUMAN
219
226
LqaEEaPe


 


2177
Q96FT7|ACCN4_HUMAN
90
97
LslEEqPl


 


2178
Q96G97|BSCL2_HUMAN
326
333
LseEEkPd


 


2179
Q96GW7|PGCB_HUMAN
880
887
LhpEEdPe


 


2180
Q96H72|S39AD_HUMAN
340
347
LleEEdPw


 


2181
Q96H78|S2544_HUMAN
265
272
LmaEEgPw


 


2182
Q96J42|TXD15_HUMAN
42
49
LwsEEqPa


 


2183
Q96JI7|SPTCS_HUMAN
1940
1947
LleEEaPd


 


2184
Q96JL9|ZN333_HUMAN
80
87
LkpEElPs


 


2185
Q96JQ0|PCD16_HUMAN
3106
3113
LyrEEgPp


 


2186
Q96MZ0|GD1L1_HUMAN
195
202
LdhEEePq


 


2187
Q96NZ9|PRAP1_HUMAN
71
78
LttEEkPr


 


2188
Q96PQ6|ZN317_HUMAN
109
116
LeqEEePr


 


2189
Q96RE7|BTB14_HUMAN
133
140
LhaEEaPs


 


2190
Q96RG2|PASK_HUMAN
1196
1203
LvfEEnPf


 


2191
Q96RL1|UIMC1_HUMAN
388
395
LllEEePt


 


2192
Q96SB3|NEB2_HUMAN
435
442
LseEEdPa


 


2193
Q96SJ8|TSN18_HUMAN
167
174
LdsEEvPe


 


2194
Q99102|MUC4_HUMAN
1306
1313
LhrEErPn


 


2195
Q99543|DNJC2_HUMAN
68
75
LqlEEfPm


 


2196
Q9BQS2|SYT15_HUMAN
36
43
LtyEElPg


 


2197
Q9BVI0|PHF20_HUMAN
483
490
LepEEsPg


 


2198
Q9BY44|EIF2A_HUMAN
461
468
LheEEpPq


 


2199
Q9BY78|RNF26_HUMAN
356
363
LneEEpPg


 


2200
Q9BYD3|RM04_HUMAN
221
228
LthEEmPq


 


2201
Q9BZA7|PC11X_HUMAN
315
322
LdrEEtPn


 


2202
Q9BZA8|PC11Y_HUMAN
347
354
LdrEEtPn


 


2203
Q9C009|FOXQ1_HUMAN
227
234
LrpEEaPg


 


2204
Q9H095|IQCG_HUMAN
122
129
LitEEgPn


 


2205
Q9H0D2|ZN541_HUMAN
149
156
LggEEpPg


 


2206
Q9H2C0|GAN_HUMAN
36
43
LdgEEiPv


 


2207
Q9H2X9|S12A5_HUMAN
681
688
LrlEEgPp


 


2208
Q9H334|FOXP1_HUMAN
291
298
LshEEhPh


 


2209
Q9H3T3|SEM6B_HUMAN
26
33
LfpEEpPp


 


2210
Q9H579|CT132_HUMAN
138
145
LvqEErPh


 


2211
Q9H5V8|CDCP1_HUMAN
788
795
LatEEpPp


 


2212
Q9H6F5|CCD86_HUMAN
227
234
LnkEElPv


 


2213
Q9H6Z4|RANB3_HUMAN
4
11
LanEEkPa


 


2214
Q9H7E9|CH033_HUMAN
94
101
LapEEvPl


 


2215
Q9H8Y1|CN115_HUMAN
137
144
LcsEEsPe


 


2216
Q9H9E1|ANRA2_HUMAN
13
20
LivEEcPs


 


2217
Q9H9F9|ARP5_HUMAN
415
422
LfsEEtPg


 


2218
Q9HAV4|XPO5_HUMAN
521
528
LnrEEiPv


 


2219
Q9HCE7|SMUF1_HUMAN
364
371
LedEElPa


 


2220
Q9NPR2|SEM4B_HUMAN
47
54
LgsEErPf


 


2221
Q9NR50|EI2BG_HUMAN
333
340
LcpEEpPv


 


2222
Q9NRJ7|PCDBG_HUMAN
200
207
LdrEEePq


 


2223
Q9NTN9|SEM4G_HUMAN
203
210
LrtEEtPm


 


2224
Q9NUR3|CT046_HUMAN
104
111
LhsEEgPa


 


2225
Q9NVR7|TBCC1_HUMAN
138
145
LigEEwPs


 


2226
Q9NX46|ARHL2_HUMAN
235
242
LgmEErPy


 


2227
Q9NYB9|ABI2_HUMAN
7
14
LleEEiPg


 


2228
Q9P1Y5|K1543_HUMAN
827
834
LlaEEtPp


 


2229
Q9P1Y5|K1543_HUMAN
938
945
LaqEEaPg


 


2230
Q9P2E7|PCD10_HUMAN
316
323
LdyEEsPv


 


2231
Q9P2K9|PTHD2_HUMAN
673
680
LevEEePv


 


2232
Q9UBB4|ATX10_HUMAN
289
296
LasEEpPd


 


2233
Q9UBN6|TR10D_HUMAN
78
85
LkeEEcPa


 


2234
Q9UBT6|POLK_HUMAN
251
258
LlfEEsPs


 


2235
Q9UGF5|OR5U1_HUMAN
303
310
LskEElPq


 


2236
Q9UGL1|JAD1B_HUMAN
879
886
LlsEEtPs


 


2237
Q9UHW9|S12A6_HUMAN
743
750
LrlEEgPp


 


2238
Q9UIF9|BAZ2A_HUMAN
609
616
LsaEEiPs


 


2239
Q9UIG0|BAZ1B_HUMAN
75
82
LlkEEfPa


 


2240
Q9ULD6|PDZD6_HUMAN
390
397
LpaEEvPl


 


2241
Q9ULG1|INOC1_HUMAN
235
242
LssEEsPr


 


2242
Q9ULI4|KI26A_HUMAN
1396
1403
LrgEEePr


 


2243
Q9ULQ1|TPC1_HUMAN
29
36
LgqEElPs


 


2244
Q9UMS0|NFU1_HUMAN
93
100
LvtEEtPs


 


2245
Q9UN72|PCDA7_HUMAN
200
207
LdrEEtPe


 


2246
Q9UN73|PCDA6_HUMAN
200
207
LdrEEaPa


 


2247
Q9UN74|PCDA4_HUMAN
200
207
LdrEEaPe


 


2248
Q9UNA0|ATS5_HUMAN
481
488
LgpEElPg


 


2249
Q9UP95|S12A4_HUMAN
678
685
LrlEEgPp


 


2250
Q9UPQ7|PZRN3_HUMAN
385
392
LlpEEhPs


 


2251
Q9UPV0|CE164_HUMAN
488
495
LatEEePp


 


2252
Q9UPW6|SATB2_HUMAN
398
405
LrkEEdPr


 


2253
Q9UPW8|UN13A_HUMAN
332
339
LeeEElPe


 


2254
Q9UPX6|K1024_HUMAN
371
378
LntEEvPd


 


2255
Q9UQ05|KCNH4_HUMAN
761
768
LlgEElPp


 


2256
Q9UQ26|RIMS2_HUMAN
201
208
LrnEEaPq


 


2257
Q9UQ26|RIMS2_HUMAN
1327
1334
LsfEEsPq


 


2258
Q9Y250|LZTS1_HUMAN
293
300
LayEErPr


 


2259
Q9Y2I6|NLP_HUMAN
759
766
LelEEpPq


 


2260
Q9Y2K7|JHD1A_HUMAN
661
668
LlnEElPn


 


2261
Q9Y2L6|FRM4B_HUMAN
438
445
LpsEEdPa


 


2262
Q9Y2V3|RX_HUMAN
126
133
LseEEqPk


 


2263
Q9Y343|SNX24_HUMAN
87
94
LenEElPk


 


2264
Q9Y3I0|CV028_HUMAN
466
473
LvmEEaPe


 


2265
Q9Y3L3|3BP1_HUMAN
130
137
LseEElPa


 


2266
Q9Y3L3|3BP1_HUMAN
494
501
LasEElPs


 


2267
Q9Y3R5|DOP2_HUMAN
1084
1091
LseEElPy


 


2268
Q9Y426|CU025_HUMAN
98
105
LsfEEdPr


 


2269
Q9Y566|SHAN1_HUMAN
1838
1845
LpwEEgPg


 


2270
Q9Y572|RIPK3_HUMAN
352
359
LnlEEpPs


 


2271
Q9Y5E2|PCDB7_HUMAN
200
207
LdrEEiPe


 


2272
Q9Y5E3|PCDB6_HUMAN
199
206
LdrEEqPq


 


2273
Q9Y5E4|PCDB5_HUMAN
200
207
LdrEErPe


 


2274
Q9Y5E5|PCDB4_HUMAN
199
206
LdrEEqPe


 


2275
Q9Y5E6|PCDB3_HUMAN
200
207
LdrEEqPe


 


2276
Q9Y5E7|PCDB2_HUMAN
202
209
LdrEEqPe


 


2277
Q9Y5F1|PCDBC_HUMAN
200
207
LdyEErPe


 


2278
Q9Y5F2|PCDBB_HUMAN
200
207
LdyEElPe


 


2279
Q9Y5F3|PCDB1_HUMAN
200
207
LdrEEqPe


 


2280
Q9Y5G1|PCDGF_HUMAN
200
207
LdrEEqPh


 


2281
Q9Y5G2|PCDGE_HUMAN
410
417
LdrEEiPe


 


2282
Q9Y5H5|PCDA9_HUMAN
200
207
LdrEEtPe


 


2283
Q9Y5I2|PCDAA_HUMAN
199
206
LdrEEnPq


 


2284
Q9Y5I3|PCDA1_HUMAN
200
207
LdrEEtPe


 


2285
Q9Y5Q9|TF3C3_HUMAN
42
49
LsaEEnPd


 


2286
Q9Y5R2|MMP24_HUMAN
201
208
LtfEEvPy
















TABLE 10







Table containing the amino acid sequence of the


peptide predicted similar to Tumstatin/Tum4









Protein Name
Peptide Location
Peptide sequence





Collagen
CAI40758.1:
LPRFSTMPFIYCNINEVCHY


type IV,
1630-1648
(SEQ ID NO: 2494)


alpha6 fibril









In other embodiments, the following peptides suitable for use with the presently disclosed subject matter are disclosed in Table 1 of International PCT Patent Application Publication Number WO2007/033215 A2 for “Compositions Having Antiangiogenic Activity and Uses Thereof,” to Popel et al., published Mar. 22, 2007, which is incorporated herein by reference in its entirety.







TABLE 11







Anti-Angiogenic Peptide sequences










SEQ ID





NO:










Thrombospondin Containing Proteins










2287
ADAM-9
Q13443: 649-661
KCHGHGVCNSNKN


 


2288
ADAM-12
O43184: 662-675
MQCHGRGVCNNRKN


 


2289
ADAMTS-1
Q9UHI8: 566-584
GPWGDCSRTCGGGVQYTMR


 


2290
ADAMTS-2
CAA05880.1: 982-998
GPWSQCSVTCGNGTQER


 


2291
ADAMTS-3
NP_055058.1: 973-989
GPWSECSVTCGEGTEVR


 


2292
ADAMTS-4
CAH72146.1: 527-540
GPWGDCSRTCGGGV


 


2293
ADAMTS-4
CAH72146.1: 527-545
GPWGDCSRTCGGGVQFSSR


 


2294
ADAMTS-5
NP_008969.1: 882-898
GPWLACSRTCDTGWHTR


 


2295
ADAMTS-6
NP_922932.2: 847-860
QPWSECSATCAGGV


 


2296
ADAMTS-6
NP_922932.2: 847-863
QPWSECSATCAGGVQRQ


 


2297
ADAMTS-7
AAH61631.1: 1576-1592
GPWGQCSGPCGGGVQRR


 


2298
ADAMTS-7
AAH61631.1: 828-841
GPWTKCTVTCGRGV


 


2299
ADAMTS-8
Q9UP79: 534-547
GPWGECSRTCGGGV


 


2300
ADAMTS-8
Q9UP79: 534-552
GPWGECSRTCGGGVQFSHR


 


2301
ADAMTS-9
Q9P2N4: 1247-1261
WSSCSVTCGQGRATR


 


2302
ADAMTS-9
Q9P2N4: 1335-1351
GPWGACSSTCAGGSQRR


 


2303
ADAMTS-9
Q9P2N4: 595-613
SPFGTCSRTCGGGIKTAIR


 


2304
ADAMTS-10
Q9H324: 528-546
TPWGDCSRTCGGGVSSSSR


 


2305
ADAMTS-12
P58397: 1479-1493
WDLCSTSCGGGFQKR


 


2306
ADAMTS-12
P58397: 549-562
SPWSHCSRTCGAGV


 


2307
ADAMTS-13
AAQ88485.1: 751-765
WMECSVSCGDGIQRR


 


2308
ADAMTS-14
CAI13857.1: 980-994
WSQCSATCGEGIQQR


 


2309
ADAMTS-15
CAC86014.1: 900-916
SAWSPCSKSCGRGFQRR


 


2310
ADAMTS-16
Q8TE57: 1133-1149
SPWSQCTASCGGGVQTR


 


2311
ADAMTS-16
Q8TE57: 1133-1150
SPWSQCTASCGGGVQTRS


 


2312
ADAMTS-18
Q8TE60: 1131-1146
PWQQCTVTCGGGVQTR


 


2313
ADAMTS-18
Q8TE60: 1131-1147
PWQQCTVTCGGGVQTRS


 


2314
ADAMTS-18
Q8TE60: 998-1014
GPWSQCSKTCGRGVRKR


 


2315
ADAMTS-18
Q8TE60: 596-614
SKWSECSRTCGGGVKFQER


 


2316
ADAMTS-19
CAC84565.1: 1096-1111
WSKCSITCGKGMQSRV


 


2317
ADAMTS-20
CAD56159.3: 1478-1494
NSWNECSVTCGSGVQQR


 


2318
ADAMTS-20
CAD56159.3: 1309-1326
GPWGQCSSSCSGGLQHRA


 


2319
ADAMTS-20
CAD56159.3: 1661-1675
WSKCSVTCGIGIMKR


 


2320
ADAMTS-20
CAD56160.2: 564-581
PYSSCSRTCGGGIESATR


 


2321
BAI-1
O14514: 361-379
SPWSVCSSTCGEGWQTRTR


 


2322
BAI-2
O60241: 304-322
SPWSVCSLTCGQGLQVRTR


 


2323
BAI-3
CAI21673.1: 352-370
SPWSLCSFTCGRGQRTRTR


 


2324
C6
AAB59433.1: 30-48
TQWTSCSKTCNSGTQSRHR


 


2325
CILP
AAQ89263.1: 156-175
SPWSKCSAACGQTGVQTRTR


 


2326
CILP-2
AAN17826.1: 153-171
GPWGPCSGSCGPGRRLRRR


 


2327
CTGF
CAC44023.1: 204-221
TEWSACSKTCGMGISTRV


 


2328
CYR61
AAR05446.1: 234-251
TSWSQCSKTCGTGISTRV


 


2329
Fibulin-6
CAC37630.1: 1574-1592
SAWRACSVTCGKGIQKRSR


 


2330
Fibulin-6
CAC37630.1: 1688-1706
QPWGTCSESCGKGTQTRAR


 


2331
Fibulin-6
CAC37630.1: 1745-1763
ASWSACSVSCGGGARQRTR


 


2332
NOVH
AAL92490.1: 211-228
TEWTACSKSCGMGFSTRV


 


2333
Papilin
NP_775733.2: 33-51
SQWSPCSRTCGGGVSFRER


 


2334
Papilin
NP_775733.2: 342-359
GPWAPCSASCGGGSQSRS


 


2335
Properdin
AAP43692.1: 143-161
GPWEPCSVTCSKGTRTRRR


 


2336
ROR-1
CAH71706.1: 313-391
CYNSTGVDYRGTVSVTKSGRQCQPWNSQYPHTHTFTALRFPEL





NGGHSYCRNPGNQKEAPWCFTLDENFKSDLCDIPAC


 


2337
ROR-1
CAH71706.1: 310-391
NHKCYNSTGVDYRGTVSVTKSGRQCQPWNSQYPHTHTFTALRF





PELNGGHSYCRNPGNQKEAPWCFTLDENFKSDLCDIPAC


 


2338
ROR-1
CAH71706.1: 311-388
HKCYNSTGVDYRGTVSVTKSGRQCQPWNSQYPHTHTFTALRFP





ELNGGHSYCRNPGNQKEAPWCFTLDENFKSDLCDI


 


2339
ROR-1
CAH71706.1: 311-391
HKCYNSTGVDYRGTVSVTKSGRQCQPWNSQYPHTHTFTALRFP





ELNGGHSYCRNPGNQKEAPWCFTLDENFKSDLCDIPAC


 


2340
ROR-1
CAH71706.1: 312-392
KCYNSTGVDYRGTVSVTKSGRQCQPWNSQYPHTHTFTALRFPE





LNGGHSYCRNPGNQKEAPWCFTLDENFKSDLCDIPACD


 


2341
ROR-2
Q01974: 315-395
QCYNGSGMDYRGTASTTKSGHQCQPWALQHPHSHHLSSTDFPE





LGGGHAYCRNPGGQMEGPWCFTQNKNVRMELCDVPSCS


 


2342
ROR-2
Q01974: 314-391
HQCYNGSGMDYRGTASTTKSGHQCQPWALQHPHSHHLSSTDFP





ELGGGHAYCRNPGGQMEGPWCFTQNKNVRMELCDV


 


2343
ROR-2
Q01974: 314-394
HQCYNGSGMDYRGTASTTKSGHQCQPWALQHPHSHHLSSTDFP





ELGGGHAYCRNPGGQMEGPWCFTQNKNVRMELCDVPSC


 


2344
ROR-2
Q01974: 314-395
HQCYNGSGMDYRGTASTTKSGHQCQPWALQHPHSHHLSSTDFP





ELGGGHAYCRNPGGQMEGPWCFTQNKNVRMELCDVPSCS


 


2345
ROR-2
Q01974: 315-394
QCYNGSGMDYRGTASTTKSGHQCQPWALQHPHSHHLSSTDFPE





LGGGHAYCRNPGGQMEGPWCFTQNKNVRMELCDVPSC


 


2346
Semaphorin 5A
NP_003957.1: 660-678
GPWERCTAQCGGGIQARRR


 


2347
Semaphorin 5A
NP_003957.1: 848-866
SPWTKCSATCGGGHYMRTR


 


2348
Semaphorin 5B
AAQ88491.1: 916-934
TSWSPCSASCGGGHYQRTR


 


2349
SCO-spondin
XP_379967.2: 3781-3799
GPWEDCSVSCGGGEQLRSR


 


2350
THSD1
AAQ88516.1: 347-365
QPWSQCSATCGDGVRERRR


 


2351
THSD3
AAH33140.1: 280-298
SPWSPCSGNCSTGKQQRTR


 


2352
THSD6
AAH40620.1: 44-60
WTRCSSSCGRGVSVRSR


 


2353
TSP-2
CAI23645.1: 444-462
SPWSSCSVTCGVGNITRIR


 


2354
TSP-2
CAI23645.1: 501-519
SPWSACTVTCAGGIRERTR


 


2355
TSRC1
AAH27478.1: 140-159
SPWSQCSVRCGRGQRSRQVR


 


2356
UNC5C
AAH41156.1: 267-285
TEWSVCNSRCGRGYQKRTR


 


2357
UNC5D
AAQ88514.1: 259-277
TEWSACNVRCGRGWQKRSR


 


2358
VSGP/F-spondin
BAB18461.1: 567-583
WDECSATCGMGMKKRHR


 


2359
VSGP/F-spondin
BAB18461.1: 621-639
SEWSDCSVTCGKGMRTRQR


 


2360
WISP-1
AAH74841.1: 221-238
SPWSPCSTSCGLGVSTRI


 


2361
WISP-2
AAQ89274.1: 199-216
TAWGPCSTTCGLGMATRV


 


2362
WISP-3
CAB16556.1: 191-208
TKWTPCSRTCGMGISNRV


 







Collagens










2363
α1CIV
CAH74130.1: 1479-1556
NERAHGQDLGTAGSCLRKFSTMPFLFCNINNVCNFASRNDYSY





WLSTPEPMPMSMAPITGENIRPFISRCAVCEAPAM


 


2364
α1CIV
CAH74130.1: 1494-1513
LRKFSTMPFLFCNINNVCNF


 


2365
α1CIV
CAH74130.1: 1504-1523
FCNINNVCNFASRNDYSYWL


 


2366
α1CIV
CAH74130.1: 1610-1628
SAPFIECHGRGTCNYYANA


 


2367
α2CIV
CAH71366.1: 1517-1593
QEKAHNQDLGLAGSCLARFSTMPFLYCNPGDVCYYASRNDKSY





WLSTTAPLPMMPVAEDEIKPYISRCSVCEAPAIA


 


2368
α2CIV
CAH71366.1: 1542-1561
YCNPGDVCYYASRNDKSYWL


 


2369
α2CIV
CAH71366.1: 1646-1664
ATPFIECNGGRGTCHYYAN


 


2370
α4CIV
CAA56943.1: 1499-1575
QEKAHNQDLGLAGSCLPVFSTLPFAYCNIHQVCHYAQRNDRSY





WLASAAPLPMMPLSEEAIRPYVSRCAVCEAPAQA


 


2371
α4CIV
CAA56943.1: 1514-1533
LPVFSTLPFAYCNIHQVCHY


 


2372
α4CIV
CAA56943.1: 1524-1543
YCNIHQVCHYAQRNDRSYWL


 


2373
α4CIV
CAA56943.1: 1628-1646
AAPFLECQGRQGTCHFFAN


 


2374
α5CIV
AAC27816.1: 1495-1572
NKRAHGQDLGTAGSCLRRFSTMPFMFCNINNVCNFASRNDYSY





WLSTPEPMPMSMQPLKGQSIQPFISRCAVCEAPAV


 


2375
α5CIV
AAC27816.1: 1510-1529
LRRFSTMPFMFCNINNVCNF


 


2376
α5CIV
AAC27816.1: 1520-1539
FCNINNVCNFASRNDYSYWL


 


2377
α5CIV
AAC27816.1: 1626-1644
SAPFIECHGRGTCNYYANS


 


2378
α6CIV
CAI40758.1: 1501-1577
QEKAHNQDLGFAGSCLPRFSTMPFIYCNINEVCHYARRNDKSY





WLSTTAPIPMMPVSQTQIPQYISRCSVCEAPSQA


 


2379
α6CIV
CAI40758.1: 1526-1545
YCNINEVCHYARRNDKSYWL


 


2380
α6CIV
CAI40758.1: 1630-1648
ATPFIECSGARGTCHYFAN


 







CXC Chemokines










2381
ENA-78/CXCL5
AAP35453.1: 86-108
NGKEICLDPEAPFLKKVIQKILD


 


2382
ENA-78/CXCL5
AAP35453.1: 48-103
RCVCLQTTQGVHPKMISNLQVFAIGPQCSKVEVVASLKNGKEIC





LDPEAPFLKKVI


 


2383
ENA-78/CXCL5
AAP35453.1: 51-107
CLQTTQGVHPKMISNLQVFAIGPQCSKVEVVASLKNGKEICLDP





EAPFLKKVIQKIL


 


2384
GCP-2/CXCL6
AAH13744.1: 86-109
NGKQVCLDPEAPFLKKVIQKILDS


 


2385
GCP-2/CXCL6
AAH13744.1: 47-106
LRCTCLRVTLRVNPKTIGKLQVFPAGPQCSKVEVVASLKNGKQV





CLDPEAPFLKKVIQKI


 


2386
GCP-2/CXCL6
AAH13744.1: 48-103
RCTCLRVTLRVNPKTIGKLQVFPAGPQCSKVEVVASLKNGKQV





CLDPEAPFLKKVI


 


2387
GCP-2/CXCL6
AAH13744.1: 51-107
CLRVTLRVNPKTIGKLQVFPAGPQCSKVEVVASLKNGKQVCLDP





EAPFLKKVIQKIL


 


2388
GRO-α/CXCL1
AAP35526.1: 80-103
NGRKACLNPASPIVKKIIEKMLNS


 


2389
GRO-α/CXCL1
AAP35526.1: 42-97
RCQCLQTLQGIHPKNIQSVNVKSPGPHCAQTEVIATLKNGRKAC





LNPASPIVKKII


 


2390
GRO-α/CXCL1
AAP35526.1: 44-101
QCLQTLQGIHPKNIQSVNVKSPGPHCAQTEVIATLKNGRKACLN





PASPIVKKIIEKML


 


2391
Gro-β/CXCL2
AAH15753.1: 42-97
RCQCLQTLQGIHLKNIQSVKVKSPGPHCAQTEVIATLKNGQKAC





LNPASPMVKKII


 


2392
GRO-γ/MIP-2β/CXCL3
AAA63184.1: 79-100
NGKKACLNPASPMVQKIIEKIL


 


2393
GRO-γ/MIP-2β/CXCL3
AAA63184.1: 43-100
QCLQTLQGIHLKNIQSVNVRSPGPHCAQTEVIATLKNGKKACLN





PASPMVQKIIEKIL


 


2394
GRO-γ/MIP-2β/CXCL3
AAA63184.1: 41-96
RCQCLQTLQGIHLKNIQSVNVRSPGPHCAQTEVIATLKNGKKAC





LNPASPMVQKII


 


2395
IL-8/CXCL8
AAP35730.1: 35-94
QCIKTYSKPFHPKFIKELRVIESGPHCANTEIIVKLSDGRELCLDP





KENWVQRVVEKFLK


 


2396
IL-8/CXCL8
AAP35730.1: 72-94
DGRELCLDPKENWVQRVVEKFLK


 


2397
IP-10/CXCL10
AAH10954.1: 29-86
RCTCISISNQPVNPRSLEKLEIIPASQFCPRVEIIATMKKKGEKRCL





NPESKAIKNLL


 


2398
MIG/CXCL9
Q07325: 32-91
SCISTNQGTIHLQSLKDLKQFAPSPSCEKIEIIATLKNGVQTCLNP





DSADVKELIKKWEK


 


2399
PF-4/CXCL4
AAK29643.1: 43-100
CVKTTSQVRPRHITSLEVIKAGPHCPTAQLIATLKNGRKICLDLQ





APLYKKIIKKLLE


 


2400
THBG-β/CXCL7
AAB46877.1: 100-121
DGRKICLDPDAPRIKKIVQKKL


 


2401
THBG-β/CXCL7
AAB46877.1: 62-117
RCMCIKTTSGIHPKNIQSLEVIGKGTHCNQVEVIATLKDGRKICL





DPDAPRIKKIV


 


2402
THBG-β/CXCL7
AAB46877.1: 64-121
MCIKTTSGIHPKNIQSLEVIGKGTHCNQVEVIATLKDGRKICLDP





DAPRIKKIVQKKL


 







Kringle Containing Proteins










2403
AK-38 protein
AAK74187.1: 14-93
DCMFGNGKGYRGKKATTVTGTPCQEWAAQEPHRHSTFIPGTNK





WAGLEKNYCRNPDGDINGPWCYTMNPRKLFDYCDIPLCA


 


2404
AK-38 protein
AAK74187.1: 12-94
QDCMFGNGKGYRGKKATTVTGTPCQEWAAQEPHRHSTFIPGTN





KWAGLEKNYCRNPDGDINGPWCYTMNPRKLFDYCDIPLCA


 


2405
AK-38 protein
AAK74187.1: 13-90
DCMFGNGKGYRGKKATTVTGTPCQEWAAQEPHRHSTFIPGTNK





WAGLEKNYCRNPDGDINGPWCYTMNPRKLFDYCDI


 


2406
AK-38 protein
AAK74187.1: 14-93
CMFGNGKGYRGKKATTVTGTPCQEWAAQEPHRHSTFIPGTNK





WAGLEKNYCRNPDGDINGPWCYTMNPRKLFDYCDIPLC


 


2407
Hageman fct/cf XII
AAM97932.1: 216-292
SCYDGRGLSYRGLARTTLSGAPCQPWASEATYRNVTAEQARN





WGLGGHAFCRNPDNDIRPWCFVLNRDRLSWEYCDL


 


2408
Hageman fct/cf XII
AAM97932.1: 214-295
KASCYDGRGLSYRGLARTTLSGAPCQPWASEATYRNVTAEQAR





NWGLGGHAFCRNPDNDIRPWCFVLNRDRLSWEYCDLAQC


 


2409
Hageman fct/cf XII
AAM97932.1: 215-296
ASCYDGRGLSYRGLARTTLSGAPCQPWASEATYRNVTAEQARN





WGLGGHAFCRNPDNDIRPWCFVLNRDRLSWEYCDLAQCQ


 


2410
HGF
P14210: 127-206
NCIIGKGRSYKGTVSITKSGIKCQPWSSMIPHEHSFLPSSYRGKDL





QENYCRNPRGEEGGPWCFTSNPEVRYEVCDIPQC


 


2411
HGF
P14210: 127-207
NCIIGKGRSYKGTVSITKSGIKCQPWSSMIPHEHSFLPSSYRGKDL





QENYCRNPRGEEGGPWCFTSNPEVRYEVCDIPQCS


 


2412
HGF
P14210: 304-377
ECIQGQGEGYRGTVNTIWNGIPCQRWDSQYPHEHDMTPENFKC





KDLRENYCRNPDGSESPWCFTTDPNIRVGYC


 


2413
HGF
P14210: 210-289
ECMTCNGESYRGLMDHTESGKICQRWDHQTPHRHKFLPERYPD





KGFDDNYCRNPDGQPRPWCYTLDPHTRWEYCAIKTCA


 


2414
HGF
P14210: 304-383
ECIQGQGEGYRGTVNTIWNGIPCQRWDSQYPHEHDMTPENFKC





KDLRENYCRNPDGSESPWCFTTDPNIRVGYCSQIPNC


 


2415
Hyaluronan
NP_004123.1: 192-277
DDCYVGDGYSYRGKMNRTVNQHACLYWNSHLLLQENYNMFM



binding

EDAETHGIGEHNFCRNPDADEKPWCFIKVTNDKVKWEYCDVSA





CS


 


2416
Hyaluronan
NP_004123.1: 192-276
DDCYVGDGYSYRGKMNRTVNQHACLYWNSHLLLQENYNMFM



binding

EDAETHGIGEHNFCRNPDADEKPWCFIKVTNDKVKWEYCDVSAC


 


2417
KREMEN-1
BAB40969.1: 31-114
ECFTANGADYRGTQNWTALQGGKPCLFWNETFQHPYNTLKYP





NGEGGLGEHNYCRNPDGDVS-





PWCYVAEHEDGVYWKYCEIPAC


 


2418
KREMEN-1
BAB40969.1: 31-115
ECFTANGADYRGTQNWTALQGGKPCLFWNETFQHPYNTLKYP





NGEGGLGEHNYCRNPDGDVSPWCYVAEHEDGVYWKYCEIPACQ


 


2419
KREMEN-2
BAD97142.1: 35-119
ECFQVNGADYRGHQNRTGPRGAGRPCLFWDQTQQHSYSSASDP





HGRWGLGAHNFCRNPDGDVQ-PWCYVAETEEGIYWRYCDIPSC


 


2420
KREMEN-2
BAD97142.1: 34-119
SECFQVNGADYRGHQNRTGPRGAGRPCLFWDQTQQHSYSSASD





PHGRWGLGAHNFCRNPDGDVQPWCYVAETEEGIYWRYCDIPSC


 


2421
Lp(a)
NP_005568.1: 1615-1690
TEQRPGVQECYHGNGQSYRGTYSTTVTGRTCQAWSSMTPHSHS





RTPEYYPNAGLIMNYCRNPDAVAAPYCYTRDPG


 


2422
Lp(a)
NP_005568.1: 3560-3639
QDCYYHYGQSYRGTYSTTVTGRTCQAWSSMTPHQHSRTPENYP





NAGLTRNYCRNPDAEIRPWCYTMDPSVRWEYCNLTQC


 


2423
Lp(a)
NP_005568.1: 4123-4201
QCYHGNGQSYRGTFSTTVTGRTCQSWSSMTPHRHQRTPENYPN





DGLTMNYCRNPDADTGPWCFTMDPSIRWEYCNLTRC


 


2424
Lp(a)
NP_005568.1: 4225-4308
EQDCMFGNGKGYRGKKATTVTGTPCQEWAAQEPHRHSTFIPGT





NKWAGLEKNYCRNPDGDINGPWCYTMNPRKLFDYCDIPLCA


 


2425
Macrophage stim. 1
AAH48330.1: 188-268
EAACVWCNGEEYRGAVDRTESGRECQRWDLQHPHQHPFEPGK





FLDQGLDDNYCRNPDGSERPWCYTTDPQIEREFCDLPRC


 


2426
Macrophage stim. 1
AAH48330.1: 368-448
QDCYHGAGEQYRGTVSKTRKGVQCQRWSAETPHKPQFTFTSEP





HAQLEENFCRNPDGDSHGPWCYTMDPRTPFDYCALRRC


 


2427
Macrophage stim. 1
AAH48330.1: 368-449
QDCYHGAGEQYRGTVSKTRKGVQCQRWSAETPHKPQFTFTSEP





HAQLEENFCRNPDGDSHGPWCYTMDPRTPFDYCALRRCA


 


2428
Macrophage stim. 1
AAH48330.1: 370-448
CYHGAGEQYRGTVSKTRKGVQCQRWSAETPHKPQFTFTSEPHA





QLEENFCRNPDGDSHGPWCYTMDPRTPFDYCALRRC


 


2429
Thrombin/cf II
AAL77436.1: 105-186
EGNCAEGLGTNYRGHVNITRSGIECQLWRSRYPHKPEINSTTHP





GADLQENFCRNPDSSTTGPWCYTTDPTVRRQECSIPVC


 


2430
Thrombin/cf II
AAL77436.1: 106-186
GNCAEGLGTNYRGHVNITRSGIECQLWRSRYPHKPEINSTTHPG





ADLQENFCRNPDSSTTGPWCYTTDPTVRRQECSIPVC


 


2431
Thrombin/cf II
AAL77436.1: 107-183
NCAEGLGTNYRGHVNITRSGIECQLWRSRYPHKPEINSTTHPGA





DLQENFCRNPDSSTTGPWCYTTDPTVRRQECSI


 


2432
Thrombin/cf II
AAL77436.1: 107-186
NCAEGLGTNYRGHVNITRSGIECQLWRSRYPHKPEINSTTHPGA





DLQENFCRNPDSSTTGPWCYTTDPTVRRQECSIPVC


 


2433
tPA
AAH95403.1: 214-293
DCYFGNGSAYRGTHSLTESGASCLPWNSMILIGKVYTAQNPSAQ





ALGLGKHNYCRNPDGDAKPWCHVLKSRRLTWEYCDV


 


2434
tPA
AAH95403.1: 213-296
SDCYFGNGSAYRGTHSLTESGASCLPWNSMILIGKVYTAQNPSA





QALGLGKHNYCRNPDGDAKPWCHVLKSRRLTWEYCDVPSC


 


2435
tPA
AAH95403.1: 213-297
SDCYFGNGSAYRGTHSLTESGASCLPWNSMILIGKVYTAQNPSA





QALGLGKHNYCRNPDGDAKPWCHVLKSRRLTWEYCDVPSCS


 


2436
tPA
AAH95403.1: 214-296
DCYFGNGSAYRGTHSLTESGASCLPWNSMILIGKVYTAQNPSAQ





ALGLGKHNYCRNPDGDAKPWCHVLKSRRLTWEYCDVPSC


 







Somatotropins










2437
GH-1
NP_000506.2: 26-160
AFPTIPLSRLFDNAMLRAHRLHQLAFDTYQEFEEAYIPKEQKYSF





LQNPQTSLCFSESIPTPSNREETQQKSNLELLRISLLLIQSWLEPVQ





FLRSVFANSLVYGASDSNVYDLLKDLEEGIQTLMGRLEDGSPR


 


2438
GH-2
CAG46700.1: 26-160
AFPTIPLSRLFDNAMLRARRLYQLAYDTYQEFEEAYILKEQKYSF





LQNPQTSLCFSESIPTPSNRAKTQQKSNLELLRISLLLIQSWLEPV





QLLRSVFANSLVYGASDSNVYRHLKDLEEGIQTLMWRLEDGSPR


 


2439
Placental
AAP35572.1: 26-160
AVQTVPLSRLFDHAMLQAHRAHQLAIDTYQEFEETYIPKDQKYS



lactogen

FLHDSQTSFCFSDSIPTPSNMEETQQKSNLELLRISLLLIESWLEPV





RFLRSMFANNLVYDTSDSDDYHLLKDLEEGIQTLMGRLEDGSRR


 


2440
Somatoliberin
AAH62475.1: 26-145
AFPTIPLSRLFDNASLRAHRLHQLAFDTYQEFNPQTSLCFSESIPT





PSMREETQQKSNLELLRISLLLIQSWLEPVQFLRSVFANSLVYGA





SDSNVYDLLKDLEEGIQTLMGRLEDGSPR


 







TIMPs










2441
TIMP 3
AAA21815.1: 148-171
ECLWTDMLSNFGYPGYQSKHYACI


 


2442
TIMP 4
AAV38433.1: 175-198
ECLWTDWLLERKLYGYQAQHYVCM









In particular embodiments, the presently disclosed subject matter provides a nanoparticle, microparticle, or gel comprising a compound of Formula (I), wherein the one or more peptide is selected from the group consisting of an isolated peptide or analog thereof comprising the amino acid sequence W-X2-C-X3-C-X2-G (SEQ ID NO: 2486), wherein X denotes a variable amino acid; W is tryptophan; C is cysteine, G is glycine; and wherein the peptide reduces blood vessel formation in a cell, tissue or organ.
In some embodiments, the one or more peptide is selected from the group consisting of an isolated peptide or analog thereof comprising or consisting essentially of a sequence having at least 85% amino acid sequence identity to an amino acid sequence selected from the group consisting of:









THSD-1:



(SEQ ID NO: 2350)



QPWSQCSATCGDGVRERRR;



 



THSD-3:



(SEQ ID NO: 2351)



SPWSPCSGNCSTGKQQRTR;



 



THSD-6:



(SEQ ID NO: 2352)



WTRCSSSCGRGVSVRSR;



 



CILP:



(SEQ ID NO: 2325) 



SPWSKCSAACGQTGVQTRTR;



 



WISP-1:



(SEQ ID NO: 2360)



SPWSPCSTSCGLGVSTRI;



 



WISP-2:



(SEQ ID NO: 2361)



TAWGPCSTTCGLGMATRV;



 



WISP-3:



(SEQ ID NO: 2362)



TKWTPCSRTCGMGISNRV;



 



F-spondin:



(SEQ ID NO: 2359)



SEWSDCSVTCGKGMRTRQR;



 



F-spondin:



(SEQ ID NO: 2358)



WDECSATCGMGMKKRHR;



 



CTGF:



(SEQ ID NO: 2327)



TEWSACSKTCGMGISTRV;



 



fibulin-6:



(SEQ ID NO: 2331)



ASWSACSVSCGGGARQRTR;



 



fibulin-6:



(SEQ ID NO: 2330)



QPWGTCSESCGKGTQTRAR;



 



fibulin-6:



(SEQ ID NO: 2329)



SAWRACSVTCGKGIQKRSR;



 



CYR61:



(SEQ ID NO: 2328)



TSWSQCSKTCGTGISTRV;



 



NOVH:



(SEQ ID NO: 2332)



TEWTACSKSCGMGFSTRV;



 



UNC5-C:



(SEQ ID NO: 2356)



TEWSVCNSRCGRGYQKRTR;



 



UNC5-D:



(SEQ ID NO: 2357)



TEWSACNVRCGRGWQKRSR;



 



SCO-spondin:



(SEQ ID NO: 2349)



GPWEDCSVSCGGGEQLRSR;



 



Properdin:



(SEQ ID NO: 2335)



GPWEPCSVTCSKGTRTRRR;



 



C6:



(SEQ ID NO: 2324)



TQWTSCSKTCNSGTQSRHR;



 



ADAMTS-like-4:



(SEQ ID NO: 2355)



SPWSQCSVRCGRGQRSRQVR;



 



ADAMTS-4:



(SEQ ID NO: 2293)



GPWGDCSRTCGGGVQFSSR;



 



ADAMTS-8:



(SEQ ID NO: 2300)



GPWGECSRTCGGGVQFSHR;



 



ADAMTS-16:



(SEQ ID NO: 2310)



SPWSQCTASCGGGVQTR;



 



ADAMTS-18:



(SEQ ID NO: 2315)



SKWSECSRTCGGGVKFQER;



 



semaphorin 5A:



(SEQ ID NO: 2346)



GPWERCTAQCGGGIQARRR;



 



semaphorin 5A:



(SEQ ID NO: 2347)



SPWTKCSATCGGGHYMRTR;



 



semaphoring 5B:



(SEQ ID NO: 2348)



TSWSPCSASCGGGHYQRTR;



 



papilin:



(SEQ ID NO: 2334)



GPWAPCSASCGGGSQSRS;



 



papilin:



(SEQ ID NO: 2333)



SQWSPCSRTCGGGVSFRER;



 



ADAM-9:



(SEQ ID NO: 2497)



KCHGHGVCNS;



and



 



ADAM-12:



(SEQ ID NO: 2288)



MQCHGRGVCNNRKN,






wherein A is alanine; I is isoleucine; M is methionine; H is histidine; Y is tyrosine; K is lysine; W is tryptophan; C is cysteine, T is threonine, S is serine; N is asparagine; G is glycine; R is arginine; V is valine, P is proline, and Q is glutamine wherein the peptide reduces blood vessel formation in a cell, tissue or organ.
In other embodiments, the one or more peptide is selected from the group consisting of an isolated peptide or analog thereof having at least 85% identity to an amino acid sequence selected from the group consisting of:









ENA-78:



(SEQ ID NO: 2381)



NGKEICLDPEAPFLKKVIQKILD;



 



CXCL6:



(SEQ ID NO: 2384)



NGKQVCLDPEAPFLKKVIQKILDS;



 



CXCL1:



(SEQ ID NO: 2388)



NGRKACLNPASPIVKKIIEKMLNS;



 



Gro-y:



(SEQ ID NO: 2392)



NGKKACLNPASPMVQKIIEKIL;



 



Beta thromboglobulin/CXCL7:



(SEQ ID NO: 2400)



DGRKICLDPDAPRIKKIVQKKL,



 



Interleukin 8 (IL-8)/CXCL8:



(SEQ ID NO: 2396)



DGRELCLDPKENWVQRVVEKFLK,



 



GCP-2:



(SEQ ID NO: 2384)



NGKQVCLDPEAPFLKKVIQKILDS,






wherein A is alanine; I is isoleucine; F is phenylalanine; D is aspartic acid; M is methionine; H is histidine; Y is tyrosine; K is lysine; W is tryptophan; C is cysteine, T is threonine, S is serine; N is asparagine; G is glycine; R is arginine; V is valine, P is proline, and Q is glutamine; and wherein the peptide reduces blood vessel formation in a cell, tissue or organ.
In yet other embodiments, the one or more peptide is selected from the group consisting of an isolated peptide or analog thereof having at least 85% amino acid sequence identity to an amino acid sequence selected from the group consisting of









Alpha 6 fibril of type 4 collagen:



(SEQ ID NO: 2379)



YCNINEVCHYARRNDKSYWL;



 



Alpha 5 fibril of type 4 collagen:



(SEQ ID NO: 2443)



LRRFSTMPFMFCNINNVCNF;



 



Alpha 4 fibril of type 4 collagen:



(SEQ ID NO: 2373)



AAPFLECQGRQGTCHFFAN;



 



Alpha 4 fibril of type 4 collagen:



(SEQ ID NO: 2371)



LPVFSTLPFAYCNIHQVCHY;



 



Alpha 4 fibril of type 4 collagen:



(SEQ ID NO: 2372)



YCNIHQVCHYAQRNDRSYWL,



and



 



Collagen type IV, a1pha6 fibril



(SEQ ID NO: 2494)



LPRFSTMPFIYCNINEVCHY;






wherein A is alanine; I is isoleucine; F is phenylalanine; D is aspartic acid; M is methionine; H is histidine; Y is tyrosine; K is lysine; W is tryptophan; C is cysteine, T is threonine, S is serine; N is asparagine; G is glycine; R is arginine; V is valine, P is proline, and Q is glutamine wherein the peptide reduces blood vessel formation in a cell, tissue or organ.
In other embodiments, peptides suitable for use in the presently disclosed subject matter are disclosed in U.S. Provisional Patent Application No. 61/421,706, filed Dec. 12, 2010, which is commonly owned, and is incorporated herein by reference in its entirety.












SEQ ID NO:
ID
Sequence







2443
SP2000
LRRFSTMPFMFCNINNVCNF


 


2444
SP2002
LRRFSTMPFMFGNINNVGNF


 


2445
SP2004
LRRFSTMPFMF


 


2446
SP2006
LRRFSTMPFMF-Abu-NINV


 


2447
SP2007
LRRFSTMPFMF-Abu


 


2448
SP2008
LRRFSTMP


 


2449
SP2009
NINNV-Abu-NF


 


2450
SP2010
FMF-Abu-NINNV-Abu-NF


 


2451
SP2011
STMPFMF-Abu-NINNV-Abu-NF


 


2452
SP2012
LRRFSTMPFMF-Abu-NINNV-Abu-NF


 


2453
SP2013
LNRFSTMPF


 


2454
SP2014
LRRFST-Nle-PF-Nle-F


 


2455
SP2015
LRRFSTMPAMF-Abu-NINNV-Abu-NF


 


2456
SP2016
LRRFSTMPFAF-Abu-NINNV-Abu-NF


 


2457
SP2017
LRRFSTMPFMA-Abu-NINNV-Abu-NF


 


2458
SP2018
LRRFSTMPF-Nle-F-Abu-NINNV-Abu-NF


 


2459
SP2019
LRRFSTMPFM(4-ClPhen)-Abu-CNINNV-




Abu-NF


 


2460
SP2020
F-Abu-NINNV-Abu-N


 


2461
SP2021
F-Abu-NIN


 


2462
SP2022
LRRFSTMPFMFSNINNVSNF


 


2463
SP2023
LRRFSTMPFMFANINNVANF


 


2464
SP2024
LRRFSTMPFMFININNVINF


 


2465
SP2025
LRRFSTMPFMFTNINNVTNF


 


2466
SP2026
LRRFSTMPFMFC(AllyGly)NINNV




(AllyGly)NF


 


2467
SP2027
LRRFSTMPFMFVNINNVVNF


 


2468
SP2028
LRRFSTMPFMF-Abu-NINN


 


2469
SP2029
LRRFSTMPFMFTNINV


 


2470
SP2030
F-Abu-NINV


 


2471
SP2031
FTNINNVTN


 


2472
SP2032
LRRFSTMPFMFTNINN


 


2473
SP2033
LRRFSTMPFMFININN


 


2474
SP2034
LRRFSTMPF-Da-FININNVINF


 


2475
SP2035
LRRFSTAPFAFININNVINF


 


2476
SP2036
LRRFSTMPFAFININNVINF;









wherein Abu is 2-aminobutyric acid; Nle is Norleucine; and AllyGly is allyglycine.

In other embodiments, peptides suitable for use in the presently disclosed subject matter are disclosed in U.S. Provisional Patent Application No. 61/489,500, filed Way 24, 2011, which also is commonly owned, and is incorporated herein by reference in its entirety.












SEQ ID NO:
ID
Sequence







2477
SP5001
RLRLLTLQSWLL


 


2478
SP5028
LMRKSQILISSWF


 


2479
SP5029
LLIVALLFILSWL


 


2480
SP5030
LLRLLLLIESWLE


 


2481
SP5031
LLRSSLILLQGSWF


 


2482
SP5032
LLHISLLLIESRLE


 


2483
SP5033
LLRISLLLIESWLE









III. Definitions
Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this presently described subject matter belongs.
While the following terms in relation to compounds of Formulae I-X are believed to be well understood by one of ordinary skill in the art, the following definitions are set forth to facilitate explanation of the presently disclosed subject matter. These definitions are intended to supplement and illustrate, not preclude, the definitions that would be apparent to one of ordinary skill in the art upon review of the present disclosure.
The terms substituted, whether preceded by the term “optionally” or not, and substituent, as used herein, refer to the ability, as appreciated by one skilled in this art, to change one functional group for another functional group provided that the valency of all atoms is maintained. When more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. The substituents also may be further substituted (e.g., an aryl group substituent may have another substituent off it, such as another aryl group, which is further substituted, for example, with fluorine at one or more positions).
When the term “independently selected” is used, the substituents being referred to (e.g., R groups, such as groups R1, R2, and the like, or variables, such as “m” and “n”), can be identical or different. For example, both R1 and R2 can be substituted alkyls, or R1 can be hydrogen and R2 can be a substituted alkyl, and the like.
A named “R” or group will generally have the structure that is recognized in the art as corresponding to a group having that name, unless specified otherwise herein. For the purposes of illustration, certain representative “R” groups as set forth above are defined below.
The term hydrocarbon, as used herein, refers to any chemical group comprising hydrogen and carbon. The hydrocarbon may be substituted or unsubstituted. As would be known to one skilled in this art, all valencies must be satisfied in making any substitutions. The hydrocarbon may be unsaturated, saturated, branched, unbranched, cyclic, polycyclic, or heterocyclic. Illustrative hydrocarbons are further defined herein below and include, for example, methyl, ethyl, n-propyl, iso-propyl, cyclopropyl, allyl, vinyl, n-butyl, tert-butyl, ethynyl, cyclohexyl, methoxy, diethylamino, and the like.
As used herein the term “alkyl” refers to C1-20 inclusive, linear (i.e., “straight-chain”), branched, or cyclic, saturated or at least partially and in some cases fully unsaturated (i.e., alkenyl and alkynyl)hydrocarbon radicals derived from a hydrocarbon moiety containing between one and twenty carbon atoms by removal of a single hydrogen atom. Representative alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, iso-pentyl, neopentyl, n-hexyl, sec-hexyl, n-heptyl, n-octyl, n-decyl, n-undecyl, dodecyl, and the like, ethenyl, propenyl, butenyl, pentenyl, hexenyl, octenyl, butadienyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, and allenyl groups. “Branched” refers to an alkyl group in which a lower alkyl group, such as methyl, ethyl or propyl, is attached to a linear alkyl chain. “Lower alkyl” refers to an alkyl group having 1 to about 8 carbon atoms (i.e., a C1-8 alkyl), e.g., 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. “Higher alkyl” refers to an alkyl group having about 10 to about 20 carbon atoms, e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms. In certain embodiments, “alkyl” refers, in particular, to C1-8 straight-chain alkyls. In other embodiments, “alkyl” refers, in particular, to C1-8 branched-chain alkyls.
Alkyl groups can optionally be substituted (a “substituted alkyl”) with one or more alkyl group substituents, which can be the same or different. The term “alkyl group substituent” includes but is not limited to alkyl, substituted alkyl, halo, arylamino, acyl, hydroxyl, aryloxyl, alkoxyl, alkylthio, arylthio, aralkyloxyl, aralkylthio, carboxyl, alkoxycarbonyl, oxo, and cycloalkyl. There can be optionally inserted along the alkyl chain one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms, wherein the nitrogen substituent is hydrogen, lower alkyl (also referred to herein as “alkylaminoalkyl”), or aryl.
Thus, as used herein, the term “substituted alkyl” includes alkyl groups, as defined herein, in which one or more atoms or functional groups of the alkyl group are replaced with another atom or functional group, including for example, alkyl, substituted alkyl, halogen, aryl, substituted aryl, alkoxyl, hydroxyl, nitro, amino, alkylamino, dialkylamino, sulfate, and mercapto.
“Cyclic” and “cycloalkyl” refer to a non-aromatic mono- or multicyclic ring system of about 3 to about 10 carbon atoms, e.g., 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. The cycloalkyl group can be optionally partially unsaturated. The cycloalkyl group also can be optionally substituted with an alkyl group substituent as defined herein, oxo, and/or alkylene. There can be optionally inserted along the cyclic alkyl chain one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms,
wherein the nitrogen substituent is hydrogen, alkyl, substituted alkyl, aryl, or substituted aryl, thus providing a heterocyclic group. Representative monocyclic cycloalkyl rings include cyclopentyl, cyclohexyl, and cycloheptyl. Multicyclic cycloalkyl rings include adamantyl, octahydronaphthyl, decalin, camphor, camphane, and noradamantyl.
The term “cycloalkylalkyl,” as used herein, refers to a cycloalkyl group as defined hereinabove, which is attached to the parent molecular moiety through an alkyl group, also as defined above. Examples of cycloalkylalkyl groups include cyclopropylmethyl and cyclopentylethyl.
The terms “cycloheteroalkyl” or “heterocycloalkyl” refer to a non-aromatic ring system, unsaturated or partially unsaturated ring system, such as a 3- to 10-member substituted or unsubstituted cycloalkyl ring system, including one or more heteroatoms, which can be the same or different, and are selected from the group consisting of N, O, and S, and optionally can include one or more double bonds. The cycloheteroalkyl ring can be optionally fused to or otherwise attached to other cycloheteroalkyl rings and/or non-aromatic hydrocarbon rings. Heterocyclic rings include those having from one to three heteroatoms independently selected from oxygen, sulfur, and nitrogen, in which the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. In certain embodiments, the term heterocylic refers to a non-aromatic 5-, 6-, or 7-membered ring or a polycyclic group wherein at least one ring atom is a heteroatom selected from O, S, and N (wherein the nitrogen and sulfur heteroatoms may be optionally oxidized), including, but not limited to, a bi- or tri-cyclic group, comprising fused six-membered rings having between one and three heteroatoms independently selected from the oxygen, sulfur, and nitrogen, wherein (i) each 5-membered ring has 0 to 2 double bonds, each 6-membered ring has 0 to 2 double bonds, and each 7-membered ring has 0 to 3 double bonds, (ii) the nitrogen and sulfur heteroatoms may be optionally oxidized, (iii) the nitrogen heteroatom may optionally be quaternized, and (iv) any of the above heterocyclic rings may be fused to an aryl or heteroaryl ring. Representative cycloheteroalkyl ring systems include, but are not limited to pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, indolinyl, quinuclidinyl, morpholinyl, thiomorpholinyl, thiadiazinanyl, tetrahydrofuranyl, and the like.
The term “alkenyl” as used herein refers to a monovalent group derived from a C1-20 inclusive straight or branched hydrocarbon moiety having at least one carbon-carbon double bond by the removal of a single hydrogen atom. Alkenyl groups include, for example, ethenyl (i.e., vinyl), propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like.
The term “cycloalkenyl” as used herein refers to a cyclic hydrocarbon containing at least one carbon-carbon double bond. Examples of cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadiene, cyclohexenyl, 1,3-cyclohexadiene, cycloheptenyl, cycloheptatrienyl, and cyclooctenyl.
The term “alkynyl” as used herein refers to a monovalent group derived from a straight or branched C1-20 hydrocarbon of a designed number of carbon atoms containing at least one carbon-carbon triple bond. Examples of “alkynyl” include ethynyl, 2-propynyl(propargyl), 1-propyne, 3-hexyne, and the like.
“Alkylene” refers to a straight or branched bivalent aliphatic hydrocarbon group having from 1 to about 20 carbon atoms, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms. The alkylene group can be straight, branched or cyclic. The alkylene group also can be optionally unsaturated and/or substituted with one or more “alkyl group substituents.” There can be optionally inserted along the alkylene group one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms (also referred to herein as “alkylaminoalkyl”), wherein the nitrogen substituent is alkyl as previously described. Exemplary alkylene groups include methylene (—CH2—); ethylene (—CH2—CH2-); propylene (—(CH2)3—); cyclohexylene (—C6H10—); —CH═CH—CH═CH—; —CH═CH—CH2—; —(CH2)q—N(R)—(CH2)r—, wherein each of q and r is independently an integer from 0 to about 20, e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, and R is hydrogen or lower alkyl; methylenedioxyl (—O—CH2—O—); and ethylenedioxyl (—O—(CH2)2—O—). An alkylene group can have about 2 to about 3 carbon atoms and can further have 6-20 carbons.
The term “aryl” is used herein to refer to an aromatic substituent that can be a single aromatic ring, or multiple aromatic rings that are fused together, linked covalently, or linked to a common group, such as, but not limited to, a methylene or ethylene moiety. The common linking group also can be a carbonyl, as in benzophenone, or oxygen, as in diphenylether, or nitrogen, as in diphenylamine. The term “aryl” specifically encompasses heterocyclic aromatic compounds. The aromatic ring(s) can comprise phenyl, naphthyl, biphenyl, diphenylether, diphenylamine and benzophenone, among others. In particular embodiments, the term “aryl” means a cyclic aromatic comprising about 5 to about 10 carbon atoms, e.g., 5, 6, 7, 8, 9, or 10 carbon atoms, and including 5- and 6-membered hydrocarbon and heterocyclic aromatic rings.
The aryl group can be optionally substituted (a “substituted aryl”) with one or more aryl group substituents, which can be the same or different, wherein “aryl group substituent” includes alkyl, substituted alkyl, alkenyl, alkynyl, aryl, substituted aryl, aralkyl, hydroxyl, alkoxyl, aryloxyl, aralkyloxyl, carboxyl, acyl, halo, haloalkyl, nitro, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acyloxyl, amino, alkylamino, dialkylamino, trialkylamino, acylamino, aroylamino, carbamoyl, cyano, alkylcarbamoyl, dialkylcarbamoyl, carboxyaldehyde, carboxyl, alkoxycarbonyl, carboxamide, arylthio, alkylthio, alkylene, thioalkoxyl, and mercapto.
Thus, as used herein, the term “substituted aryl” includes aryl groups, as defined herein, in which one or more atoms or functional groups of the aryl group are replaced with another atom or functional group, including for example, alkyl, substituted alkyl, halogen, aryl, substituted aryl, alkoxyl, hydroxyl, nitro, amino, alkylamino, dialkylamino, sulfate, and mercapto.
Specific examples of aryl groups include, but are not limited to, cyclopentadienyl, phenyl, furan, thiophene, pyrrole, pyran, pyridine, imidazole, benzimidazole, isothiazole, isoxazole, pyrazole, pyrazine, triazine, pyrimidine, quinoline, isoquinoline, indole, carbazole, and the like.
The terms “heteroaryl” and “aromatic heterocycle” and “aromatic heterocyclic” are used interchangeably herein and refer to a cyclic aromatic radical having from five to ten ring atoms of which one ring atom is selected from sulfur, oxygen, and nitrogen; zero, one, or two ring atoms are additional heteroatoms independently selected from sulfur, oxygen, and nitrogen; and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the ring atoms, such as, for example, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, and the like. Aromatic heterocyclic groups can be unsubstituted or substituted with substituents selected from the group consisting of branched and unbranched alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, trialkylamino, acylamino, cyano, hydroxy, halo, mercapto, nitro, carboxyaldehyde, carboxy, alkoxycarbonyl, and carboxamide. Specific heterocyclic and aromatic heterocyclic groups that may be included in the compounds of the invention include: 3-methyl-4-(3-methylphenyl)piperazine, 3 methylpiperidine, 4-(bis-(4-fluorophenyl)methyl)piperazine, 4-(diphenylmethyl)piperazine, 4(ethoxycarbonyl)piperazine, 4-(ethoxycarbonylmethyl)piperazine, 4-(phenylmethyl)piperazine, 4-(1-phenylethyl)piperazine, 4-(1,1-dimethylethoxycarbonyl)piperazine, 4-(2-(bis-(2-propenyl)amino)ethyl)piperazine, 4-(2-(diethylamino)ethyl)piperazine, 4-(2-chlorophenyl)piperazine, 4(2-cyanophenyl)piperazine, 4-(2-ethoxyphenyl)piperazine, 4-(2-ethylphenyl)piperazine, 4-(2-fluorophenyl)piperazine, 4-(2-hydroxyethyl)piperazine, 4-(2-methoxyethyl)piperazine, 4-(2-methoxyphenyl)piperazine, 4-(2-methylphenyl)piperazine, 4-(2-methylthiophenyl)piperazine, 4(2-nitrophenyl)piperazine, 4-(2-nitrophenyl)piperazine, 4-(2-phenylethyl)piperazine, 4-(2-pyridyl)piperazine, 4-(2-pyrimidinyl)piperazine, 4-(2,3-dimethylphenyl)piperazine, 4-(2,4-difluorophenyl)piperazine, 4-(2,4-dimethoxyphenyl)piperazine, 4-(2,4-dimethylphenyl)piperazine, 4-(2,5-dimethylphenyl)piperazine, 4-(2,6-dimethylphenyl)piperazine, 4-(3-chlorophenyl)piperazine, 4-(3-methylphenyl)piperazine, 4-(3-trifluoromethylphenyl)piperazine, 4-(3,4-dichlorophenyl)piperazine, 4-(3,4-dimethoxyphenyl)piperazine, 4-(3,4-dimethylphenyl)piperazine, 4-(3,4-methylenedioxyphenyl)piperazine, 4-(3,4,5-trimethoxyphenyl)piperazine, 4-(3,5-dichlorophenyl)piperazine, 4-(3,5-dimethoxyphenyl)piperazine, 4-(4-(phenylmethoxy)phenyl)piperazine, 4-(4-(3,1-dimethylethyl)phenylmethyl)piperazine, 4-(4-chloro-3-trifluoromethylphenyl)piperazine, 4-(4-chlorophenyl)-3-methylpiperazine, 4-(4-chlorophenyl)piperazine, 4-(4-chlorophenyl)piperazine, 4-(4-chlorophenylmethyl)piperazine, 4-(4-fluorophenyl)piperazine, 4-(4-methoxyphenyl)piperazine, 4-(4-methylphenyl)piperazine, 4-(4-nitrophenyl)piperazine, 4-(4-trifluoromethylphenyl)piperazine, 4-cyclohexylpiperazine, 4-ethyl piperazine, 4-hydroxy-4-(4-chlorophenyl)methylpiperidine, 4-hydroxy-4-phenylpiperidine, 4-hydroxypyrrolidine, 4-methylpiperazine, 4-phenylpiperazine, 4-piperidinylpiperazine, 4-(2-furanyl)carbonyl)piperazine, 4-((1,3-dioxolan-5-yl)methyl)piperazine, 6-fluoro-1,2,3,4-tetrahydro-2-methylquinoline, 1,4-diazacylcloheptane, 2,3-dihydroindolyl, 3,3-dimethylpiperidine, 4,4-ethylenedioxypiperidine, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline, azacyclooctane, decahydroquinoline, piperazine, piperidine, pyrrolidine, thiomorpholine, and triazole. The heteroaryl ring can be fused or otherwise attached to one or more heteroaryl rings, aromatic or non-aromatic hydrocarbon rings, or heterocycloalkyl rings. A structure represented generally by the formula:




as used herein refers to a ring structure, for example, but not limited to a 3-carbon, a 4-carbon, a 5-carbon, a 6-carbon, a 7-carbon, and the like, aliphatic and/or aromatic cyclic compound, including a saturated ring structure, a partially saturated ring structure, and an unsaturated ring structure, comprising a substituent R group, wherein the R group can be present or absent, and when present, one or more R groups can each be substituted on one or more available carbon atoms of the ring structure. The presence or absence of the R group and number of R groups is determined by the value of the variable “n,” which is an integer generally having a value ranging from 0 to the number of carbon atoms on the ring available for substitution. Each R group, if more than one, is substituted on an available carbon of the ring structure rather than on another R group. For example, the structure above where n is 0 to 2 would comprise compound groups including, but not limited to:





and the like.

A dashed line representing a bond in a cyclic ring structure indicates that the bond can be either present or absent in the ring. That is, a dashed line representing a bond in a cyclic ring structure indicates that the ring structure is selected from the group consisting of a saturated ring structure, a partially saturated ring structure, and an unsaturated ring structure.
When a named atom of an aromatic ring or a heterocyclic aromatic ring is defined as being “absent,” the named atom is replaced by a direct bond.
As used herein, the term “acyl” refers to an organic acid group wherein the —OH of the carboxyl group has been replaced with another substituent and has the general formula RC(═O)—, wherein R is an alkyl, alkenyl, alkynyl, aryl, carbocylic, heterocyclic, or aromatic heterocyclic group as defined herein). As such, the term “acyl” specifically includes arylacyl groups, such as an acetylfuran and a phenacyl group. Specific examples of acyl groups include acetyl and benzoyl.
The terms “alkoxyl” or “alkoxy” are used interchangeably herein and refer to a saturated (i.e., alkyl-O—) or unsaturated (i.e., alkenyl-O— and alkynyl-O—) group attached to the parent molecular moiety through an oxygen atom, wherein the terms “alkyl,” “alkenyl,” and “alkynyl” are as previously described and can include C1-C20 inclusive, linear, branched, or cyclic, saturated or unsaturated oxo-hydrocarbon chains, including, for example, methoxyl, ethoxyl, propoxyl, isopropoxyl, n-butoxyl, sec-butoxyl, t-butoxyl, and n-pentoxyl, neopentoxy, n-hexoxy, and the like.
The term “alkoxyalkyl” as used herein refers to an alkyl-O-alkyl ether, for example, a methoxyethyl or an ethoxymethyl group.
“Aryloxyl” refers to an aryl-O— group wherein the aryl group is as previously described, including a substituted aryl. The term “aryloxyl” as used herein can refer to phenyloxyl or hexyloxyl, and alkyl, substituted alkyl, halo, or alkoxyl substituted phenyloxyl or hexyloxyl.
“Aralkyl” refers to an aryl-alkyl-group wherein aryl and alkyl are as previously described, and included substituted aryl and substituted alkyl. Exemplary aralkyl groups include benzyl, phenylethyl, and naphthylmethyl.
“Aralkyloxyl” refers to an aralkyl-O— group wherein the aralkyl group is as previously described. An exemplary aralkyloxyl group is benzyloxyl.
“Alkoxycarbonyl” refers to an alkyl-O—CO— group. Exemplary alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, butyloxycarbonyl, and t-butyloxycarbonyl.
“Aryloxycarbonyl” refers to an aryl-O—CO— group. Exemplary aryloxycarbonyl groups include phenoxy- and naphthoxy-carbonyl.
“Aralkoxycarbonyl” refers to an aralkyl-O—CO— group. An exemplary aralkoxycarbonyl group is benzyloxycarbonyl.
“Carbamoyl” refers to an amide group of the formula —CONH2. “Alkylcarbamoyl” refers to a R′RN—CO— group wherein one of R and R′ is hydrogen and the other of R and R′ is alkyl and/or substituted alkyl as previously described. “Dialkylcarbamoyl” refers to a R′RN—CO— group wherein each of R and R′ is independently alkyl and/or substituted alkyl as previously described.
The term carbonyldioxyl, as used herein, refers to a carbonate group of the formula —O—CO—OR.
“Acyloxyl” refers to an acyl-O— group wherein acyl is as previously described.
The term “amino” refers to the —NH2 group and also refers to a nitrogen containing group as is known in the art derived from ammonia by the replacement of one or more hydrogen radicals by organic radicals. For example, the terms “acylamino” and “alkylamino” refer to specific N-substituted organic radicals with acyl and alkyl substituent groups respectively.
The terms alkylamino, dialkylamino, and trialkylamino as used herein refer to one, two, or three, respectively, alkyl groups, as previously defined, attached to the parent molecular moiety through a nitrogen atom. The term alkylamino refers to a group having the structure —NHR′ wherein R′ is an alkyl group, as previously defined; whereas the term dialkylamino refers to a group having the structure —NR′R′′, wherein R′ and R′′ are each independently selected from the group consisting of alkyl groups. The term trialkylamino refers to a group having the structure —NR′R′′R′′′, wherein R′, R′′, and R′′′ are each independently selected from the group consisting of alkyl groups. Additionally, R′, R′′, and/or R′′′ taken together may optionally be —(CH2)k— where k is an integer from 2 to 6. Examples include, but are not limited to, methylamino, dimethylamino, ethylamino, diethylamino, diethylaminocarbonyl, methylethylamino, iso-propylamino, piperidino, trimethylamino, and propylamino.
The terms alkylthioether and thioalkoxyl refer to a saturated (i.e., alkyl-S—) or unsaturated (i.e., alkenyl-S— and alkynyl-S—) group attached to the parent molecular moiety through a sulfur atom. Examples of thioalkoxyl moieties include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, and the like.
“Acylamino” refers to an acyl-NH— group wherein acyl is as previously described. “Aroylamino” refers to an aroyl-NH— group wherein aroyl is as previously described.
The term “carbonyl” refers to the —(C═O)— group. The term “carboxyl” refers to the —COOH group. Such groups also are referred to herein as a “carboxylic acid” moiety.
The terms “halo,” “halide,” or “halogen” as used herein refer to fluoro, chloro, bromo, and iodo groups.
The term “hydroxyl” refers to the —OH group.
The term “hydroxyalkyl” refers to an alkyl group substituted with an —OH group.
The term “mercapto” refers to the —SH group.
The term “oxo” refers to a compound described previously herein wherein a carbon atom is replaced by an oxygen atom.
The term “nitro” refers to the —NO2 group.
The term “thio” refers to a compound described previously herein wherein a carbon or oxygen atom is replaced by a sulfur atom.
The term “sulfate” refers to the —SO4 group.
The term thiohydroxyl or thiol, as used herein, refers to a group of the formula —SH.
The term ureido refers to a urea group of the formula —NH—CO—NH2.
Throughout the specification and claims, a given chemical formula or name shall encompass all tautomers, congeners, and optical- and stereoisomers, as well as racemic mixtures where such isomers and mixtures exist.
As used herein the term “monomer” refers to a molecule that can undergo polymerization, thereby contributing constitutional units to the essential structure of a macromolecule or polymer.
A “polymer” is a molecule of high relative molecule mass, the structure of which essentially comprises the multiple repetition of unit derived from molecules of low relative molecular mass, i.e., a monomer.
As used herein, an “oligomer” includes a few monomer units, for example, in contrast to a polymer that potentially can comprise an unlimited number of monomers. Dimers, trimers, and tetramers are non-limiting examples of oligomers.
Further, as used herein, the term “nanoparticle,” refers to a particle having at least one dimension in the range of about 1 nm to about 1000 nm, including any integer value between 1 nm and 1000 nm (including about 1, 2, 5, 10, 20, 50, 60, 70, 80, 90, 100, 200, 500, and 1000 nm and all integers and fractional integers in between). In some embodiments, the nanoparticle has at least one dimension, e.g., a diameter, of about 100 nm. In some embodiments, the nanoparticle has a diameter of about 200 nm. In other embodiments, the nanoparticle has a diameter of about 500 nm. In yet other embodiments, the nanoparticle has a diameter of about 1000 nm (1 μm). In such embodiments, the particle also can be referred to as a “microparticle. Thus, the term “microparticle” includes particles having at least one dimension in the range of about one micrometer (μm), i.e., 1×10−6 meters, to about 1000 μm. The term “particle” as used herein is meant to include nanoparticles and microparticles.
It will be appreciated by one of ordinary skill in the art that nanoparticles suitable for use with the presently disclosed methods can exist in a variety of shapes, including, but not limited to, spheroids, rods, disks, pyramids, cubes, cylinders, nanohelixes, nanosprings, nanorings, rod-shaped nanoparticles, arrow-shaped nanoparticles, teardrop-shaped nanoparticles, tetrapod-shaped nanoparticles, prism-shaped nanoparticles, and a plurality of other geometric and non-geometric shapes. In particular embodiments, the presently disclosed nanoparticles have a spherical shape.
The subject treated by the presently disclosed methods in their many embodiments is desirably a human subject, although it is to be understood that the methods described herein are effective with respect to all vertebrate species, which are intended to be included in the term “subject.” Accordingly, a “subject” can include a human subject for medical purposes, such as for the treatment of an existing condition or disease or the prophylactic treatment for preventing the onset of a condition or disease, or an animal subject for medical, veterinary purposes, or developmental purposes. Suitable animal subjects include mammals including, but not limited to, primates, e.g., humans, monkeys, apes, and the like; bovines, e.g., cattle, oxen, and the like; ovines, e.g., sheep and the like; caprines, e.g., goats and the like; porcines, e.g., pigs, hogs, and the like; equines, e.g., horses, donkeys, zebras, and the like; felines, including wild and domestic cats; canines, including dogs; lagomorphs, including rabbits, hares, and the like; and rodents, including mice, rats, and the like. An animal may be a transgenic animal. In some embodiments, the subject is a human including, but not limited to, fetal, neonatal, infant, juvenile, and adult subjects. Further, a “subject” can include a patient afflicted with or suspected of being afflicted with a condition or disease. Thus, the terms “subject” and “patient” are used interchangeably herein.
“Associated with”: When two entities are “associated with” one another as described herein, they are linked by a direct or indirect covalent or non-covalent interaction. Preferably, the association is covalent. Desirable non-covalent interactions include hydrogen bonding, van der Waals interactions, hydrophobic interactions, magnetic interactions, electrostatic interactions, etc.
“Biocompatible”: The term “biocompatible”, as used herein is intended to describe compounds that are not toxic to cells. Compounds are “biocompatible” if their addition to cells in vitro results in less than or equal to 20% cell death, and their administration in vivo does not induce inflammation or other such adverse effects.
“Biodegradable”: As used herein, “biodegradable” compounds are those that, when introduced into cells, are broken down by the cellular machinery or by hydrolysis into components that the cells can either reuse or dispose of without significant toxic effect on the cells (i.e., fewer than about 20% of the cells are killed when the components are added to cells in vitro). The components preferably do not induce inflammation or other adverse effects in vivo. In certain preferred embodiments, the chemical reactions relied upon to break down the biodegradable compounds are uncatalyzed.
“Effective amount”: In general, the “effective amount” of an active agent or drug delivery device refers to the amount necessary to elicit the desired biological response. As will be appreciated by those of ordinary skill in this art, the effective amount of an agent or device may vary depending on such factors as the desired biological endpoint, the agent to be delivered, the composition of the encapsulating matrix, the target tissue, and the like.
“Peptide” or “protein”: A “peptide” or “protein” comprises a string of at least three amino acids linked together by peptide bonds. The terms “protein” and “peptide” may be used interchangeably. Peptide may refer to an individual peptide or a collection of peptides. Inventive peptides preferably contain only natural amino acids, although non-natural amino acids (i.e., compounds that do not occur in nature but that can be incorporated into a polypeptide chain) and/or amino acid analogs as are known in the art may alternatively be employed. Also, one or more of the amino acids in an inventive peptide may be modified, for example, by the addition of a chemical entity such as a carbohydrate group, a phosphate group, a farnesyl group, an isofarnesyl group, a fatty acid group, a linker for conjugation, functionalization, or other modification, etc. In a preferred embodiment, the modifications of the peptide lead to a more stable peptide (e.g., greater half-life in vivo). These modifications may include cyclization of the peptide, the incorporation of D-amino acids, etc. None of the modifications should substantially interfere with the desired biological activity of the peptide.
“Polynucleotide” or “oligonucleotide”: Polynucleotide or oligonucleotide refers to a polymer of nucleotides. Typically, a polynucleotide comprises at least three nucleotides. The polymer may include natural nucleosides (i.e., adenosine, thymidine, guanosine, cytidine, uridine, deoxyadenosine, deoxythymidine, deoxyguanosine, and deoxycytidine), nucleoside analogs (e.g., 2-aminoadenosine, 2-thiothymidine, inosine, pyrrolo-pyrimidine, 3-methyl adenosine, C5-propynylcytidine, C5-propynyluridine, C5-bromouridine, C5-fluorouridine, C5-iodouridine, C5-methylcytidine, 7-deazaadenosine, 7-deazaguanosine, 8-oxoadenosine, 8-oxoguanosine, 0(6)-methylguanine, and 2-thiocytidine), chemically modified bases, biologically modified bases (e.g., methylated bases), intercalated bases, modified sugars (e.g., 2′-fluororibose, ribose, 2′-deoxyribose, arabinose, and hexose), or modified phosphate groups (e.g., phosphorothioates and 5′-N-phosphoramidite linkages).
“Small molecule”: As used herein, the term “small molecule” refers to organic compounds, whether naturally-occurring or artificially created (e.g., via chemical synthesis) that have relatively low molecular weight and that are not proteins, polypeptides, or nucleic acids. Typically, small molecules have a molecular weight of less than about 1500 g/mol. Also, small molecules typically have multiple carbon-carbon bonds. Known naturally-occurring small molecules include, but are not limited to, penicillin, erythromycin, taxol, cyclosporin, and rapamycin. Known synthetic small molecules include, but are not'limited to, ampicillin, methicillin, sulfamethoxazole, and sulfonamides.
By “analog” is meant a chemical compounds having a structure that is different from the general structure of a reference agent, but that functions in a manner similar to the reference agent. For example, a peptide analog having a variation in sequence or having a modified amino acid.
By “thrombospondin (TSP) derived peptide” is meant a peptide comprising a TSP motif: W-X(2)-C-X(3)-C-X(2)-G (SEQ ID NO: 2486). Exemplary TSP derived peptides are shown in Tables 1 and 2. If desired, the peptide includes at least about 5, 10, 20, 30, 40, 50 or more amino acids that flank the carboxy or amino terminus of the motif in the naturally occurring amino acid sequence of the peptide. TSP1 derived peptides include, for example, those derived from proteins WISP-1 (SPWSPCSTSCGLGVSTRI (SEQ ID NO: 2360)), NOVH (TEWTACSKSCGMGFSTRV (SEQ ID NO: 2332)) and UNC5C (TEWSVCNSRCGRGYQKRTR (SEQ ID NO: 2356)).
By “CXC derived peptide” is meant a peptide comprising a CXC Motif: G-X(3)-C-L. Exemplary CXC derived peptides are shown in Table 3. If desired, the peptide includes at least about 5, 10, 20, 30, 40, 50 or more amino acids that flank the carboxy or amino terminus of the motif in the naturally occurring amino acid sequence. CXC derived peptides include, for example, those derived from proteins GRO-α/CXCL1 (NGRKACLNPASPIVKKIIEKMLNS (SEQ ID NO: 2388)) GRO-γ/MIP-2β/CXCL3 (NGKKACLNPASPMVQKIIEKIL (SEQ ID NO: 2392)), and ENA-78/CXCL5 (NGKEICLDPEAPFLKKVIQKILD (SEQ ID NO: 2381)).
By “Collagen IV derived peptide” is meant a peptide comprising a C-N-X(3)-V-C (SEQ ID NO:2487)) or P-F-X(2)-C collagen motif. Exemplary collagen IV derived peptides are shown in Table 5. If desired, the peptide includes at least about 5, 10, 20, 30, 40, 50 or more amino acids that flank the carboxy or amino terminus of the motif in the naturally occurring amino acid sequence. Type IV collagen derived peptides include, for example, LRRFSTMPFMFCNINNVCNF (SEQ ID NO: 2375)and FCNINNVCNFASRNDYSYWL, (SEQ ID NO: 2365)) and LPRFSTMPFIYCNINEVCHY (SEQ ID NO: 2494).
By “Somatotropin derived peptide” is meant a peptide comprising a Somatotropin Motif: L-X(3)-L-L-X(3)-S—X-L (SEQ ID NO: 2488). Exemplary somatotropin derived peptides are shown in Table 8. If desired, the peptide includes at least about 5, 10, 20, 30, 40, 50 or more amino acids that flank the carboxy or amino terminus of the motif in the naturally occurring amino acid sequence.
By “Serpin derived peptide” is meant a peptide comprising a Serpin Motif: L-X(2)-E-E-X-P (SEQ ID NO: 2489). Exemplary serpin derived peptides are shown in Table 9. If desired, the peptide includes at least about 5, 10, 20, 30, 40, 50 or more amino acids that flank the carboxy or amino terminus of the motif in the naturally occurring amino acid sequence.
By “Beta 1 integrin” is meant a polypeptide that binds a collagen IV derived peptide or that has at least about 85% identity to NP_596867 or a fragment thereof.
By “Beta 3 integrin” is meant a polypeptide that binds a collagen IV derived peptide or that has at least about 85% identity to P05106 or a fragment thereof.
By “CD36” is meant a CD36 glycoprotein that binds to a thrombospondin-derived peptide or that has at least about 85% identity to NP_001001548 or a fragment thereof. CD36 is described, for example, by Oquendo et al., “CD36 directly mediates cytoadherence of Plasmodium falciparum parasitized erythrocytes,” Cell 58: 95-101, 1989.
By “CD47” is meant a CD47 glycoprotein that binds to a thrombospondin-derived peptides or that has at least about 85% identity to NP_000315 or a fragment thereof. CD47 is described, for example, by Han et al., “CD47, a ligand for the macrophage fusion receptor, participates in macrophage multinucleation.” J. Biol. Chem. 275: 37984-37992, 2000.
By “CXCR3” is meant a G protein coupled receptor or fragment thereof having at least about 85% identity to NP_001495. CXCR3 is described, for example, by Trentin et al., “The chemokine receptor CXCR3 is expressed on malignant B cells and mediates chemotaxis.” J. Clin. Invest. 104: 115-121, 1999.
By “blood vessel formation” is meant the dynamic process that includes one or more steps of blood vessel development and/or maturation, such as angiogenesis, vasculogenesis, formation of an immature blood vessel network, blood vessel remodeling, blood vessel stabilization, blood vessel maturation, blood vessel differentiation, or establishment of a functional blood vessel network.
By “angiogenesis” is meant the growth of new blood vessels originating from existing blood vessels. Angiogenesis can be assayed by measuring the total length of blood vessel segments per unit area, the functional vascular density (total length of perfused blood vessel per unit area), or the vessel volume density (total of blood vessel volume per unit volume of tissue).
By “vasculogenesis” is meant the development of new blood vessels originating from stem cells, angioblasts, or other precursor cells.
By “blood vessel stability” is meant the maintenance of a blood vessel network.
By “alteration” is meant a change in the sequence or in a modification (e.g., a post-translational modification) of a gene or polypeptide relative to an endogeneous wild-type reference sequence.
By “ameliorate” is meant decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease.
By “antibody” is meant any immunoglobulin polypeptide, or fragment thereof, having immunogen binding ability.
In this disclosure, “comprises,” “comprising,” “containing” and “having” and the like can have the meaning ascribed to them in U.S. Patent law and can mean “includes,” “including,” and the like; “consisting essentially of or “consists essentially” likewise has the meaning ascribed in U.S. Patent law and the term is open-ended, allowing for the presence of more than that which is recited so long as basic or novel characteristics of that which is recited is not changed by the presence of more than that which is recited, but excludes prior art embodiments.
A “cancer” in an animal refers to the presence of cells possessing characteristics typical of cancer-causing cells, for example, uncontrolled proliferation, loss of specialized functions, immortality, significant metastatic potential, significant increase in anti-apoptotic activity, rapid growth and proliferation rate, and certain characteristic morphology and cellular markers. In some circumstances, cancer cells will be in the form of a tumor; such cells may exist locally within an animal, or circulate in the blood stream as independent cells, for example, leukemic cells.
By “disease” is meant any condition or disorder that damages or interferes with the normal function of a cell, tissue, or organ.
By “fragment” is meant a portion of a polypeptide or nucleic acid molecule. This portion contains, preferably, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of the entire length of the reference nucleic acid molecule or polypeptide. A fragment may contain 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000 nucleotides or amino acids.
By “isolated nucleic acid molecule” is meant a nucleic acid (e.g., a DNA) that is free of the genes, which, in the naturally occurring genome of the organism from which the nucleic acid molecule of the invention is derived, flank the gene. The term therefore includes, for example, a recombinant DNA that is incorporated into a vector; into an autonomously replicating plasmid or virus; or into the genomic DNA of a prokaryote or eukaryote; or that exists as a separate molecule (for example, a cDNA or a genomic or cDNA fragment produced by PCR or restriction endonuclease digestion) independent of other sequences. In addition, the term includes an RNA molecule which is transcribed from a DNA molecule, as well as a recombinant DNA which is part of a hybrid gene encoding additional polypeptide sequence.
By an “isolated polypeptide” is meant a polypeptide of the invention that has been separated from components that naturally accompany it. Typically, the polypeptide is isolated when it is at least 60%, by weight, free from the proteins and naturally-occurring organic molecules with which it is naturally associated. Preferably, the preparation is at least 75%, more preferably at least 90%, and most preferably at least 99%, by weight, a polypeptide of the invention. An isolated polypeptide of the invention may be obtained, for example, by extraction from a natural source, by expression of a recombinant nucleic acid encoding such a polypeptide; or by chemically synthesizing the protein. Purity can be measured by any appropriate method, for example, column chromatography, polyacrylamide gel electrophoresis, or by HPLC analysis.
By “marker” is meant any protein or polynucleotide having an alteration in expression level or activity that is associated with a disease or disorder.
“By “neoplasia” is meant a disease that is caused by or results in inappropriately high levels of cell division, inappropriately low levels of apoptosis, or both. Solid tumors, hematological disorders, and cancers are examples of neoplasias.
By “operably linked” is meant that a first polynucleotide is positioned adjacent to a second polynucleotide that directs transcription of the first polynucleotide when appropriate molecules (e.g., transcriptional activator proteins) are bound to the second polynucleotide.
By “peptide” is meant any fragment of a polypeptide. Typically peptide lengths vary between 5 and 1000 amino acids (e.g., 5, 10, 15, 20, 25, 50, 100, 200, 250, 500, 750, and 1000).
By “polypeptide” is meant any chain of amino acids, regardless of length or post-translational modification.
By “promoter” is meant a polynucleotide sufficient to direct transcription. By “reduce” is meant a decrease in a parameter (e.g., blood vessel formation) as detected by standard art known methods, such as those described herein. As used herein, reduce includes a 10% change, preferably a 25% change, more preferably a 40% change, and even more preferably a 50% or greater change.
By “reference” is meant a standard or control condition.
By “substantially identical” is meant a polypeptide or nucleic acid molecule exhibiting at least 50% identity to a reference amino acid sequence (for example, any one of the amino acid sequences described herein) or nucleic acid sequence (for example, any one of the nucleic acid sequences described herein). Preferably, such a sequence is at least 60%, more preferably 80% or 85%, and even more preferably 90%, 95% or even 99% identical at the amino acid level or nucleic acid to the sequence used for comparison.
Sequence identity is typically measured using sequence analysis software (for example, Sequence Analysis Software Package of the Genetics Computer Group, University of Wisconsin Biotechnology Center, 1710 University Avenue, Madison, Wis. 53705, BLAST, BESTFIT, GAP, or PILEUP/PRETTYBOX programs). Such software matches identical or similar sequences by assigning degrees of homology to various substitutions, deletions, and/or other modifications. Conservative substitutions typically include substitutions within the following groups: glycine, alanine; valine, isoleucine, leucine; aspartic acid, glutamic acid, asparagine, glutamine; serine, threonine; lysine, arginine; and phenylalanine, tyrosine. In an exemplary approach to determining the degree of identity, a BLAST program may be used, with a probability score between e−3 and e−100 indicating a closely related sequence.
“Sequence identity” or “identity” in the context of two nucleic acid or polypeptide sequences includes reference to the residues in the two sequences which are the same when aligned for maximum correspondence over a specified comparison window, and can take into consideration additions, deletions and substitutions. When percentage of sequence identity is used in reference to proteins it is recognized that residue positions which are not identical often differ by conservative amino acid substitutions, where amino acid residues are substituted for other amino acid residues with similar chemical properties (for example, charge or hydrophobicity) and therefore do not deleteriously change the functional properties of the molecule. Where sequences differ in conservative substitutions, the percent sequence identity may be adjusted upwards to correct for the conservative nature of the substitution. Sequences which differ by such conservative substitutions are said to have sequence similarity. Approaches for making this adjustment are well-known to those of skill in the art. Typically this involves scoring a conservative substitution as a partial rather than a full mismatch, thereby increasing the percentage sequence identity. Thus, for example, where an identical amino acid is given a score of 1 and a non-conservative substitution is given a score of zero, a conservative substitution is given a score between zero and 1. The scoring of conservative substitutions is calculated, for example, according to the algorithm of Meyers and Miller, Computer Applic. Biol. Sci., 4: 11-17, 1988, for example, as implemented in the program PC/GENE (Intelligenetics, Mountain View, Calif., USA).
“Percentage of sequence identity” means the value determined by comparing two optimally aligned sequences over a comparison window, wherein the portion of the polynucleotide sequence in the comparison window may comprise additions, substitutions, or deletions (i.e., gaps) as compared to the reference sequence (which does not comprise additions, substitutions, or deletions) for optimal alignment of the two sequences. The percentage is calculated by determining the number of positions at which the identical nucleic acid base or amino acid residue occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the window of comparison and multiplying the result by 100 to yield the percentage of sequence identity.
The term “substantial identity” or “homologous” in their various grammatical forms in the context of polynucleotides means that a polynucleotide comprises a sequence that has a desired identity, for example, at least 60% identity, preferably at least 70% sequence identity, more preferably at least 80%, still more preferably at least 90% and even more preferably at least 95%, compared to a reference sequence using one of the alignment programs described using standard parameters. One of skill will recognize that these values can be appropriately adjusted to determine corresponding identity of proteins encoded by two nucleotide sequences by taking into account codon degeneracy, amino acid similarity, reading frame positioning and the like. Substantial identity of amino acid sequences for these purposes normally means sequence identity of at least 60%, more preferably at least 70%, 80%, 85%, 90%, and even more preferably at least 95%.
Another indication that nucleotide sequences are substantially identical is if two molecules hybridize to each other under stringent conditions. However, nucleic acids which do not hybridize to each other under stringent conditions are still substantially identical if the polypeptides which they encode are substantially identical. This may occur, for example, when a copy of a nucleic acid is created using the maximum codon degeneracy permitted by the genetic code. One indication that two nucleic acid sequences are substantially identical is that the polypeptide which the first nucleic acid encodes is immunologically cross reactive with the polypeptide encoded by the second nucleic acid, although such cross-reactivity is not required for two polypeptides to be deemed substantially identical.
An “expression vector” is a nucleic acid construct, generated recombinantly or synthetically, bearing a series of specified nucleic acid elements that enable transcription of a particular gene in a host cell. Typically, gene expression is placed under the control of certain regulatory elements, including constitutive or inducible promoters, tissue-preferred regulatory elements, and enhancers.
A “recombinant host” may be any prokaryotic or eukaryotic cell that contains either a cloning vector or expression vector. This term also includes those prokaryotic or eukaryotic cells that have been genetically engineered to contain the cloned gene(s) in the chromosome or genome of the host cell.
The term “operably linked” is used to describe the connection between regulatory elements and a gene or its coding region. That is, gene expression is typically placed under the control of certain regulatory elements, including constitutive or inducible promoters, tissue-specific regulatory elements, and enhancers. Such a gene or coding region is said to be “operably linked to” or “operatively linked to” or “operably associated with” the regulatory elements, meaning that the gene or coding region is controlled or influenced by the regulatory element.
A “reference sequence” is a defined sequence used as a basis for sequence comparison. A reference sequence may be a subset of or the entirety of a specified sequence; for example, a segment of a full-length cDNA or gene sequence, or the complete cDNA or gene sequence. For polypeptides, the length of the reference polypeptide sequence will generally be at least about 5, 10, or 15 amino acids, preferably at least about 20 amino acids, more preferably at least about 25 amino acids, and even more preferably about 35 amino acids, about 50 amino acids, about 100 amino acids, or about 150 amino acids. For nucleic acids, the length of the reference nucleic acid sequence will generally be at least about 50 nucleotides, preferably at least about 60 nucleotides, more preferably at least about 75 nucleotides, and even more preferably about 100 nucleotides about 300 nucleotides or about 450 nucleotides or any integer thereabout or therebetween.
Methods of alignment of sequences for comparison are well-known in the art. Optimal alignment of sequences for comparison may be conducted by the local homology algorithm of Smith and Waterman, Adv. Appl. Math., 2: 482, 1981; by the homology alignment algorithm of Needleman and Wunsch, J. Mol. Biol., 48: 443, 1970; by the search for similarity method of Pearson and Lipman, Proc. Natl. Acad. Sci. USA, 8: 2444, 1988; by computerized implementations of these algorithms, including, but not limited to: CLUSTAL in the PC/Gene program by Intelligenetics, Mountain View, Calif., GAP, BESTFIT, BLAST, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group (GCG), 7 Science Dr., Madison, Wis., USA; the CLUSTAL program is well described by Higgins and Sharp, Gene, 73: 237-244, 1988; Corpet, et al., Nucleic Acids Research, 16:10881-10890, 1988; Huang, et al., Computer Applications in the Biosciences, 8:1-6, 1992; and Pearson, et al., Methods in Molecular Biology, 24:7-331, 1994. The BLAST family of programs which can be used for database similarity searches includes: BLASTN for nucleotide query sequences against nucleotide database sequences; BLASTX for nucleotide query sequences against protein database sequences; BLASTP for protein query sequences against protein database sequences; TBLASTN for protein query sequences against nucleotide database sequences; and TBLASTX for nucleotide query sequences against nucleotide database sequences. See, Current Protocols in Molecular Biology, Chapter 19, Ausubel, et al., Eds., Greene Publishing and Wiley-Interscience, New York, 1995. New versions of the above programs or new programs altogether will undoubtedly become available in the future, and can be used with the present invention.
Unless otherwise stated, sequence identity/similarity values provided herein refer to the value obtained using the BLAST 2.0 suite of programs, or their successors, using default parameters (Altschul et al., Nucleic Acids Res, 2:3389-3402, 1997). It is to be understood that default settings of these parameters can be readily changed as needed in the future.
As those ordinary skilled in the art will understand, BLAST searches assume that proteins can be modeled as random sequences. However, many real proteins comprise regions of nonrandom sequences which may be homopolymeric tracts, short-period repeats, or regions enriched in one or more amino acids. Such low-complexity regions may be aligned between unrelated proteins even though other regions of the protein are entirely dissimilar. A number of low-complexity filter programs can be employed to reduce such low-complexity alignments. For example, the SEG (Wooten and Federhen, Comput. Chem., 17:149-163, 1993) and XNU (Clayerie and States, Comput. Chem., 17:191-1, 1993) low-complexity filters can be employed alone or in combination.
As used herein, the terms “treat,” “treating,” “treatment,” and the like refer to reducing or ameliorating a disorder and/or symptoms associated therewith. It will be appreciated that, although not precluded, treating a disorder or condition does not require that the disorder, condition or symptoms associated therewith be completely eliminated.
A “tumor,” as used herein, refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all precancerous and cancerous cells and tissues.
As used herein, the terms “prevent,” “preventing,” “prevention,” “prophylactic treatment” and the like refer to reducing the probability of developing a disorder or condition in a subject, who does not have, but is at risk of or susceptible to developing a disorder or condition.
Following long-standing patent law convention, the terms “a,” “an,” and “the” refer to “one or more” when used in this application, including the claims. Thus, for example, reference to “a subject” includes a plurality of subjects, unless the context clearly is to the contrary (e.g., a plurality of subjects), and so forth.
Throughout this specification and the claims, the terms “comprise,” “comprises,” and “comprising” are used in a non-exclusive sense, except where the context requires otherwise. Likewise, the term “include” and its grammatical variants are intended to be non-limiting, such that recitation of items in a list is not to the exclusion of other like items that can be substituted or added to the listed items.
For the purposes of this specification and appended claims, unless otherwise indicated, all numbers expressing amounts, sizes, dimensions, proportions, shapes, formulations, parameters, percentages, parameters, quantities, characteristics, and other numerical values used in the specification and claims, are to be understood as being modified in all instances by the term “about” even though the term “about” may not expressly appear with the value, amount or range. Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are not and need not be exact, but may be approximate and/or larger or smaller as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art depending on the desired properties sought to be obtained by the presently disclosed subject matter. For example, the term “about,” when referring to a value can be meant to encompass variations of, in some embodiments, ±100% in some embodiments ±50%, in some embodiments ±20%, in some embodiments ±10%, in some embodiments ±5%, in some embodiments ±1%, in some embodiments ±0.5%, and in some embodiments ±0.1% from the specified amount, as such variations are appropriate to perform the disclosed methods or employ the disclosed compositions.
Further, the term “about” when used in connection with one or more numbers or numerical ranges, should be understood to refer to all such numbers, including all numbers in a range and modifies that range by extending the boundaries above and below the numerical values set forth. The recitation of numerical ranges by endpoints includes all numbers, e.g., whole integers, including fractions thereof, subsumed within that range (for example, the recitation of 1 to 5 includes 1, 2, 3, 4, and 5, as well as fractions thereof, e.g., 1.5, 2.25, 3.75, 4.1, and the like) and any range within that range.
EXAMPLES
The following Examples have been included to provide guidance to one of ordinary skill in the art for practicing representative embodiments of the presently disclosed subject matter. In light of the present disclosure and the general level of skill in the art, those of skill can appreciate that the following Examples are intended to be exemplary only and that numerous changes, modifications, and alterations can be employed without departing from the scope of the presently disclosed subject matter. The following Examples are offered by way of illustration and not by way of limitation.
Example 1
Methods
Synthesis of BR6
All chemicals were purchased from Sigma-Aldrich Chemical Co. (St. Louis, Mo., USA) and used without further purification. Bis(2-hydroxyethyl)disulfide (15.4 g, 10 mmol) and triethylamine (TEA, 37.5 mL, 300 mmol) were dissolved in 450 mL of tetrahydrofuran previously dried with NaSO4 in a 1000 ml round bottom flask. The flask was flushed with N2 for 10 min and then maintained under a N2 environment. Acryloyl chloride (24.4 mL, 300 mmol) was dissolved in 50 mL tetrahydrofuran then added to the flask dropwise over 2 hrs while stirring. The reaction was carried out for 24 hrs, then the TEA HCl precipitate was removed by filtration, and the solvent was removed by rotary evaporation. The product was dissolved in 100 mL dichloromethane and washed five times with 200 mL of an aqueous solution of 0.2 M Na2CO3 and three times with distilled water. The solution was dried with NaSO4 and the solvent was removed by rotary evaporation.
Polymer Synthesis
Base monomer BR6 was polymerized with side chain monomers S3, S4, and S5 at a base:side chain ratio of 1.2:1 by weight without solvent at 90° C. for 24 hrs while stirring. For end-capping with E10, base polymer was dissolved in anhydrous dimethyl sulfoxide at 100 mg/mL with 0.2 mM end-cap. The reaction was allowed to proceed for 1 hr at room temperature while shaking.
Example 2
Characteristics of Representative Polymer/Peptide Nanoparticles
Referring now to FIG. 5 are shown representative formation and sizing of polymer/peptide nanoparticles (by nanoparticle tracking analysis on a Nanosight LM10). Selected peptides and PBAEs were diluted in 25 mM sodium acetate buffer and then together in different weight-to-weight ratios. In some embodiments w/w is unity, 1:1, in other embodiments there is an excess of polymer to peptide. In some embodiments this ratio is 5:1, in other embodiments between 1:1-10:1, in other embodiments it is 10:1 to 20:1. In FIG. 6, both a 5:1 and 1:1 ratio is shown. The mixtures were incubated at room temperature for up to 10 minutes to allow for self-assembly and then loaded into the NanoSight laser cell. Using NanoSight nanoparticle tracking software and analysis, individual particles were tracked in order to determine the average size distribution of the particles. In the case of more hydrophilic peptides (DEAH Box poly8 (“DEAH” disclosed as SEQ ID NO: 2484)) and PBAEs (336), there were very few background particles, that is very few particles of peptide or PBAE only. However, when self-assembled, a noticeable nanoparticle distribution was observed, with an average size ranging from 100-150 nm. In the case of hydrophobic peptides and PBAEs, they have the possibility of aggregating with themselves. In the case of the peptide-PBAE mixture, a shift in the mean can be observed as a way to detect difference in nanoparticle formation.
Referring now to FIG. 6, is shown DEAH peptide (SEQ ID NO: 2484) release by 336 nanoparticles at 4° C. (above) and 37° C. (below). Changing polymer to peptide formulation ratios and concentrations are key to tune release. Slowing the reaction rate of degradation of the liable polymer bonds extends release from nanoparticles. This is shown by change in temperature, but could also be accomplished by increasing hydrophobicity of the polymer, increasing the molecular weight between liable ester groups, or other modifications known by someone in the art; FITC labeled DEAH peptide (SEQ ID NO: 2484) and 336 polymer were mixed and incubated for up to 10 minutes in sodium acetate buffer. Mixtures at different peptide concentrations, but constant polymer to peptide ratios, as well as peptide only were added to a 96-well plate. Fluorescence measurements were obtained using a plate reader and measured over time. The plates were kept either at 4° C. or 37° C.
Referring now to FIG. 7, is shown HUVEC viability/proliferation assays with polymer/SP6001/DEAH peptide (“DEAH” disclosed as SEQ ID NO: 2484); the CellTiter 96® AQueous One Solution Cell Proliferation assay was used to see the effect of both peptide and polymer on cell proliferation and viability. Polymers at the right concentrations have minimal cytotoxic effect on the cells, such as 336 below 100 uM. The individual peptides and Polymers were diluted in sodium acetate buffer and added to HUVECs in a 96-well plate. After incubating for a few days, the assay substrate was added and then incubated for a few hours at 37° C. Absorbance measurements were performed using a plate reader.
Referring now to FIG. 8 is shown HUVEC migration assays with 336 polymer/DEAH peptide (“DEAH” disclosed as SEQ ID NO: 2484). These nanoparticles inhibit endothelial migration in addition to proliferation and viability. Peptide-polymer nanoparticles were made as described previously. Samples were added to HUVEC cells and migration was measured using the ACEA time course cell migration system. Nanoparticle formulations at a total peptide concentration of 20 uM were able to inhibit migration more than any peptide only at 20 μM.
Referring now to FIG. 9 is shown in vivo 336 polymer nanoparticle/SP6001 DEAH peptide (“DEAH” disclosed as SEQ ID NO: 2484,); Peptide-336 polymer nanoparticles were formulated as previously described and intravitreously injected to test in vivo efficacy. ACNV laser mouse model was used on C57 BL/6 female mice. The mice receive laser eye treatments on day zero, followed by the intravitreous injections. Mice are then perfused with fluorescein labeled dextran on day 14 and choroidal flat mounts (bottom) were analyzed via fluorescence microscopy. On day 14, both the peptide only and nanoparticles formulations significantly reduced angiogenesis in the eye (top) and did so to a similar extent. This suggests that all peptide was released from nanoparticles by day 14.
Referring now to FIG. 10 is shown (top) Particle size and (bottom) cell viability effects of various polymer/SP2012 nanoparticles as compared to peptide only of non-cytotoxic polymers; a range of polymer structures were mixed with SP2000 series peptides, in a similar manner as described above. Similar sizing is found with peptides from the same class with similar structural properties. For example, SP2000, SP2012, SP2024, SP2034, and SP2036 can be encapsulated similarly to each other with the same polymers, but different from peptides from other classes such as SP6001. Sizing was performed using the Malzern Zetasizer. Size strongly depends on polymer choice. Using the same cell viability assay as described previously, effects of nanoparticle vs. peptide only on HUVECs in a 96-well plate. Non-cytotoxic polymers are shown here. Referring once again to FIG. 10, the (top) panel suggests that some of these peptide-polymer formulations have an increased effect on HUVEC cell proliferation and viability (y-axis ratio less than one) as compared to peptide only. (Data also are normalized to any polymer-only effects. Pep-pol/pol/SP2012 refers to the change in cell proliferation/viability due to the peptide/polymer nanoparticle formulation divided by any change in cell proliferation/viability from the same dose of polymer by itself and this quantity divided by the change in cell proliferation/viability by delivering the same amount of peptide SP2012 as a bolus);
FIG. 11 shows polymer/peptide formulations for alternative peptides. Peptide-polymer formulations made as described previously. Here two different classes of peptides are used. Experiments performed in a 96-well plate, with final results obtained using the same cell viability/proliferation assay as described previously. An increased effect (decreased metabolic activity) is observed for the nanoparticle formulations over the free peptide.
Example 3
Hydrogels for Protein/Peptide Release
As shown in FIG. 12, FITC-tagged bovine serum albumin (BSA) was mixed with a macromer solution containing 10% (w/v) PEGDA (Mn-270 Da) with various amounts of B4S4, dissolved in a 1:1 (v/v) mixture of DMSO and PBS. Irgacure 2959 was added at 0.05% (w/v), and the solution was briefly vortexed and immediately polymerized to form gels. The gels were incubated at 37° C. in 1×PBS with shaking. PBS was removed at each time point to measure fluorescence.
The observed slowed release is due to two factors: first, increased overall hydrophobicity can decrease the movement of water in and out of the gel, reducing degradation rate and protein release. Furthermore, this method of mixing relatively hydrophobic diacrylates with hydrophilic diacrylates in a co-solvent (mixture of water and DMSO) that can dissolve both types of polymer causes the spontaneous formation of micro-emulsions within the gel (see SEM in FIG. 13; increasing B4S4 from top [0.2% w/w] to bottom [5% w/w]). Similar to traditionally studied controlled-release microparticles, these microparticles within photopolymerized gels could serve as another way to tune the release of an encapsulated peptide, protein, or drug.
Example 4
Stable Formulations
In this formulation nanoparticles were formed by mixing PBAE and DNA in 25 mM sodium acetate buffer (pH 5) at a 30:1 polymer:DNA ratio (w/w). After 10 min of incubation, sucrose solution was added at various concentrations. The particles were mixed, then frozen at −80° C. for 1 hr and lyophilized for 48 hr. They then were used for transfection or sizing or were stored at either room temperature, 4° C. or −20° C. and tested at various timepoints.
Referring now to FIG. 14, the size distribution of appropriately freeze-dried particles (bottom left, right-most histogram) remains the same as freshly-prepared particles (bottom left, left-most histogram). Freeze-dried particles also remain more stable in serum-containing medium than freshly-prepared particles (upper left). Using DNA-loaded nanoparticles, transfection efficiency is comparable between fresh particles and particles lyophilized with sucrose (right) even after 3 months of storage. Modifying type of sugar and concentration of sugar modulates the stability of the degradable nanoparticles.
Example 5
Inclusion of Lyophilized Nanoparticles into Pellets/Scaffolds
For coating of natural or pre-made synthetic scaffolds, DNA nanoparticles were prepared by mixing DNA and polymer in a sodium acetate buffer. Sucrose was added for a final concentration of 15 mg/mL, and the solution was used to coat the surface of a trabecular bone construct. This construct was then lyophilized for 2 days before being seeded with primary human cells ( ̃50% GFP+ for ease of visualization). Referring now to FIG. 15, DsRed expression was observed within 24 hr, indicating that the nanoparticles remained functional and able to transfect cells in this new system.
Lyophilized nanoparticles also can be mixed with PLGA microparticles to form a larger construct that can be more easily manipulated and also can tune controlled release properties. In this embodiment, DsRed DNA-containing nanoparticles were compressed into a pellet with PLGA microparticles. This pellet was then placed within a well containing primary human glioblastoma cells ( ̃20% GFP+ for ease of visualization through the opaque pellet). Referring now to FIG. 16, DsRed expression was observed within 4 days and remained very robust even after 12 days. Referring once again to FIG. 16, top=1 day, middle=4 days, bottom=12 days after transfection.
Further, as demonstrated in FIG. 17, DNA-loaded nanoparticles have been incorporated into natural and synthetic scaffolds, disks, microparticles, and hydrogels.
Example 6
Bioreducible Polymeric Particle Formulations for Delivery of siRNA
Reducible functional groups mediate successful siRNA-delivery, including transfection. In this example, GFP+ primary human glioblastoma cells were seeded in 96-well plates at a density of 104 cells/well in complete culture medium (DMEM/F-12 with 10% FBS and 1% antibiotic-antimycotic) and allowed to adhere overnight. Just before transfection, the culture medium was changed to serum-free medium. Particles were prepared by diluting polymer and siRNA both in 25 mM sodium acetate buffer (pH 5), then mixing them at a 100:1 polymer:siRNA ratio (w/w). Nanoparticles formed spontaneously after 10 min of incubation and were added to the cells in medium at a 1:5 ratio (v/v) and a final concentration of 60 nM. Each polymer/siRNA treatment group was paired with a control group using a scrambled siRNA sequence (scrRNA). Cells were incubated with the particles for 4 hr. The medium and particles were then aspirated and replaced with complete medium. On each of the following days, GFP expression was measured using a Synergy 2 multiplate fluorescence reader (Biotek). Background fluorescence was measured from GFP cells in medium and was subtracted from all other readings. Knockdown was calculated by normalizing GFP fluorescence (excitation 485 nm, emission 528 nm) from the siRNA-treated cells to the scrRNA-treated cells. Medium was changed every 3 days.
The reducible disulfide bond in the endgroup E10 (cystamine dihydrochloride) drastically improves siRNA delivery and gene knockdown. Referring now to FIG. 18, GFP+ glioblastoma cells were transfected with scrambled (control) siRNA (top panels) or siRNA against GFP (bottom). The polymers used as transfection agents consisted of B3-S5 at a 1.1:1 molar ratio, endcapped with (from left to right) E10, E3 (1,3=diaminopentane), or E6 (2-(3-aminopropylamino)ethanol). With the endgroups tested, the base polymer B3-S5 was able to achieve up to 8% knockdown; with E10 as the endgroup, over 80% knockdown was observed.
Referring now to FIGS. 19A-19C, the activity of R6-series polymers at delivering siRNA to knockdown GFP signal is GB cells is further demonstrated. % Knockdown of GFP expression in GFP+ glioblastoma cells transfected with siRNA against GFP, normalized to cells transfected with scrambled siRNA, using various BR6 polymers as a transfection agent. (A) Transfection with acrylate-terminated BR6 polymers with either S3, S4 or S5 as the side chain; (B) Transfection with E10 end-capped versions of the polymers in Figure A; and (C) GFP fluorescence images of cells transfected with BR6-S4-Ac complexed scrambled RNA (top) vs. siRNA against GFP (bottom);
Without wishing to be bound to any one particular theory, it is likely that E10 facilitates siRNA delivery by augmenting intracellular release because it degrades in the reducing intracellular environment. Results from gel retardation assay supports this hypothesis. Gel retardation assays were carried out by adding polymer of varying concentrations in sodium acetate buffer to a constant concentration of siRNA in sodium acetate. After 10 min of incubation, a solution of 30% glycerol in water was added at a 1:5 volumetric ratio as a loading buffer. Bromophenol blue or other dyes were not added, as they were found to interfere with binding. Samples were loaded into a 1% agarose gel with 1 μg/mL ethidium bromide at 125 ng siRNA per well. Samples were run for 15 min under 100 V, then visualized using UV exposure.
Referring now to FIG. 20, a gel retardation assay of siRNA with BR6-S5-E10 at varying ratios of polymer to RNA is shown. The polymer effectively retards siRNA (top), but in the presence of 5 mM glutathione siRNA is released immediately (bottom). These data demonstrate the hypothesized intracellular release of siRNA and elucidates the mechanism by which nanoparticles formed using BR6 facilitate strong siRNA transfection and GFP knockdown.
Referring also to FIG. 21, an E10-endcapped polymer (top) retards siRNA efficiently, but upon addition of 5 mM glutathione, siRNA is immediately released (bottom). Numbers refer to the w/w ratio of polymer-to-siRNA in all cases.
Referring now to FIG. 22, the same polymer as in FIG. 21, but with a different endcap (E7, 1-(3-aminopropyl)-4-methylpiperazine) also retards siRNA (top), but is not affected by application of glutathione (bottom).
Referring now to FIG. 23, gel permeation chromatography data of BR6 polymerized with S4 at a BR6:S4 ratio of 1.2:1 at 90° C. for 24 hours, before and after end-capping with E7, are provided.
Referring now to FIG. 24, knockdown efficiency also is affected by molecular weight of the polymer. In FIG. 24, 1.2:1, 1.1:1, and 1.05:1 refer to the ratio of reactants in the base polymer step growth reaction, which affects the ultimate molecular weight. Top 4310 formulations were able to achieve greater knockdown over time compared to commercially available reagents like Lipofectamine 2000 (Lipo).
Referring now to FIG. 25, combined DNA (RFP) and siRNA delivery (against GFP) in GB; GFP+GB cells were treated with scrambled siRNA (top) or siRNA against GFP (bottom), causing visible knockdown. Interestingly, different polymer structures seem ideal for siRNA versus DNA delivery or for both. One polymer effective in both was used to deliver both siRNA against GFP and plasmid DsRed DNA to GFP+ hMSCs, resulting in the ability to turn green cells red.
Referring now to FIG. 26, siRNA knockdown is affected by the endcap (E), base polymer (increasing hydrophobicity from L to R within each E), and molecular weight (increasing L to R within each base polymer). One endcap that shows high knockdown even at lower molecular weights is E10, which is strikingly more effective than the other endcaps tested for the same base polymers. Other PBAEs were also highly effective when synthesized at high molecular weight.
Referring now to FIG. 27, is shown 4410, 200 w/w (blue line on above graph), 8 days after transfection: Left: hMSCs treated with scrambled control; Right: hMSCs treated with siRNA.
Referring now to FIG. 28, in some embodiments, polymer molecular weight is between 4.00-10.00 kDa for siRNA delivery.
Example 7
DNA Delivery
Referring now to FIG. 29, the presently disclosed biomaterial can be used for other forms of delivery, for example DNA delivery. DNA transfection shows some similar trends compared with siRNA, but with different optimal endcaps. Specific polymer structure is critical to determine which polymers are effective for DNA delivery or siRNA delivery or both. Both DNA and siRNA transfection depend less on MW with high polymer hydrophobicity. High GFP DNA delivery was achieved using PBAEs, with transfection in 10% serum and at 5 μg DNA/mL. Referring now to FIG. 30, several formulations with up to 90% transfection and high (>90%) viability are shown.
Referring now to FIG. 31, GB transfection is demonstrated. More particularly, 551 GB cells cultured as neurospheres (undifferentiated). They were plated in monolayer on laminin 24 hr before transfection with DsRed DNA using 447 LG (red). 48 hr after transfection, they were stained for nestin (blue). Red and blue overlaid (left) show that transfection occurred in nestin+ cells (nestin only: right).
Referring now to FIG. 32, for a DNA delivery application, in some embodiments, polymer molecular weight is between 3.00-10.0 kDa.
Example 8
In Vivo Activity for Selected Peptides
In some embodiments, the presently disclosed subject matter demonstrates in vivo activity for selected peptides in DIVAA angioreactors and a lung cancer xenograft model, Koskimaki J E, Karagiannis E D, Tang B C, Hammers H, Watkins D N, Pili R, et al. Pentastatin-1, a collagen IV derived 20-mer peptide, suppresses tumor growth in a small cell lung cancer xenograft model. BMC Cancer 2010; 10:29, and in a breast cancer xenograft model using MDA-MB-231 cells. Koskimaki J E, Karagiannis E D, Rosca E V, Vesuna F, Winnard P T, Jr., Raman V, et al. Peptides derived from type IV collagen, CXC chemokines, and thrombospondin-1 domain-containing proteins inhibit neovascularization and suppress tumor growth in MDA-MB-231 breast cancer xenografts. Neoplasia 2009;11(12):1285-91.
Following orthotopic inoculation of SCID mice in the mammary fat pad area using 2×106 cells, tumors grew to approximately 100 mm3 in 2 weeks; at that time 100 μL of peptide solution was injected i.p. once a day at peptide doses 10-20 mg/kg. PBS solution was injected as control. Several peptides have been found to inhibit tumor growth. See FIG. 33A. The microvessel density was determined by screening the immunohistologically stained CD31 sections. Inhibition of LEC migration in the ACEA migration assay also was determined (see FIG. 33B).
Representative data showing the activity of free peptide and peptide encapsulated in the presently disclosed polymeric particles are shown in FIG. 33D, which shows the metabolic activity of free peptides and peptides in polymeric particles.
Example 9
Non-viral Gene Delivery for Treatment of Glioblastoma and Brain Cancer Stem Cells
Glioblastoma (GB) is a grade IV brain cancer as defined by the WHO and is the most common primary CNS tumor in the United States. Current treatment includes surgical resection, radiotherapy, and chemotherapy. The median survival with treatment is approximately 14 months.
Brain cancer stem cells (BCSCs) possess genetic and morphological features similar to neural stem cells. Small numbers of BCSCs can initiate gliomas. BCSCs are refactory to conventional anti-cancer treatments.
Gene delivery typically is accomplished by either vaccine-mediated or polymer mediates techniques. Virus-mediated gene delivery is highly efficient, insertional mutagenesis, and toxicity/immunogenicity. Polymer-mediated gene delivery is chemically versatile, potentially safer than vaccine-mediated gene delivery, but typically is less efficient. See Green et al., 2008. Acc. Chem. Res. 41(6):749-59; Putnam 2006. Nat. Mater. 5(6):439-51.
Non-viral, e.g., polymer-mediated gene delivery, can be accomplished, in some embodiments, by using poly(beta-amino esters) (PBAEs). In particular embodiments, PBAEs suitable for use in target delivery can be synthesized in a two-step reaction provided herein below in Scheme 6 and can form nanocomplexes with negatively-charged cargo (e.g., DNA, siRNA) via electrostatic interactions as disclosed, for example, in some embodiments described in International PCT Patent Application Publication No. WO/2010/132879 for “Multicomponent Degradable Cationic Polymers,” to Green et al., which is incorporated herein by reference in its entirety.




In some embodiments, the presently disclosed subject matter demonstrates the delivery of DNA to GB cells, i.e., bulk tumor (non-stem cells; verifies the efficacy of the presently disclosed methods in BCSCs; demonstrates the delivery of apoptosis-inducing genes in BCSCs; provides practical considerations for translation of the presently disclosed methods; and discusses how the presently disclosed methods can be used in conjunction with other methods for treating GB.
The delivery of DNA to GB cells, bulk tumor (non-stem cells) and the efficacy of the presently disclosed methods to deliver DNA to BCSCs is demonstrated in FIGS. 36-39.
Referring now to FIG. 34, the delivery of DNA to GB bulk tumor cells is demonstrated for representative biomaterials. Referring now to FIG. 35, the transfection of genes to BCSC is demonstrated for representative presently disclosed biomaterials. FIG. 36 demonstrates the delivery of DNA to fetal (healthy) cells. FIG. 37 also demonstrates the delivery of DNA to BCSCs. The delivery of apoptosis-inducing genes in BCSCs is demonstrated in FIGS. 38 to 39.
These data demonstrate that PBAEs can be used for highly effective DNA delivery to GB cells, including tumor-initiating stem cells; transfection occurs even in 3D neurospheres in suspension; transfection is much less efficient in non-cancer cells (F34 fetal cells) as compared to GB cells; and transfection with secreted TRAIL causes more death in BCSCs with not significant effect on healthy cells.
In practical considerations for translation, for lyophilized nanoparticles, the presently disclosed methods provide an ease of preparation, e.g., only water needs to be added to the lyophilized nanoparticles, long-term storage, large, consistent batches, manipulation for uses in other devices, and stability in suspension. See scheme in FIG. 3.
As shown in FIG. 40, particles lyophilized with sucrose and used immediately are as effective in transfection as freshly prepared particles. Further, no loss in efficiency is observed within three months; and approximately 50% efficiency is retained after six months. The use of the presently disclosed materials and methods for long-term gene delivery is demonstrated in FIGS. 41 and 42. Other methods for treatment of GB include siRNA delivery to GB cells (FIG. 43).
A comparison of siRNA vs. DNA delivery in GB cells is shown in FIGS. 44 and 45. More particularly, as shown in FIG. 45, both 4410 and 447 can form complexes with DNA and siRNA; a higher weight ratio of polymer-to-nucleic acid is needed for siRNA than for DNA; E10 polymers release siRNA immediately, but not DNA, upon addition of glutathione (GSH).
In summary, PBAE/nucleic acid nanoparticles can be fabricated in a form that remains stable over time and allow flexibility for clinical use; PBAEs can be used for effective DNA or siRNA delivery to GB-derived BCSCs; and efficient release of cargo is necessary for effective nucleic acid delivery, especially with siRNA.
Example 10
Microparticles for Peptide Delivery In some embodiments, microparticles for controlled release of nanoparticles, which themselves encapsulate biological agents, are illustrated in FIGS. 14-17.
More particularly, FIG. 46 depicts a strategy of combining nanoparticles within microparticles to extend release further. PLGA or blends of PLGA can be combined with the presently disclosed polymers to form microparticles by double emulsion. FIG. 47 shows release of a representative peptide, DEAH-FITC, (“DEAH” disclosed as SEQ ID NO: 2484), from a presently disclosed microparticle. FIG. 48 shows slow extended release from microparticles containing nanoparticles that contain peptides; FITC-DEAH peptide (“DEAH” disclosed as SEQ ID NO: 2484 ) was first mixed with the 336 PBAE to allow for self-assembly into nanoparticles and was then mixed with BSA (middle) or not (bottom) to form an aqueous mixture. This mixture was added to a DCM-PLGA phase and sonicated to form a w/o suspension. This suspension was then added to a PVA solution and homogenized to form the final w/o/w suspension. This mixture was finally added to another PVA solution to allow for the DCM to evaporate and harden the formed microparticle. Different release profiles can potentially be obtained as seen above for the different microparticle formulations. In all cases, there is a long-term release of the peptide. Forming nanoparticles that encapsulate the peptide within the microparticles, extends the release compared to encapsulating peptide directly into microparticles (middle figure). The particles can be designed to have different release depending on the local environment (top figure). In some embodiments, release is constant over time and zero-order with respect to time (bottom figure).
Referring now to FIG. 49 in shown the in vivo effects of microparticle formulations in both the CNV and rhoNEGF model over time. DEAH (SP6001)-336 PBAE nanoparticle formulation made as described previously (“DEAH” disclosed as SEQ ID NO: 2484). (Top) Intravitreal injections into CNV model mice as described previously show comparable effects after 14 days, even though only small fraction of peptide is released over that time from microparticles. (Middle) and (Bottom) A genetic model of wet form of age-related macular degeneration in mice used to test long-term effect of microparticles. After 1 week (middle) comparable effects seen in reduction of angiogenesis. After 8 weeks (bottom), however, while peptide only no longer inhibits angiogenesis, the microparticle still does, as it is still releasing peptide over this time. While PLGA is used to form the microparticles used above, other polymers may be used including the synthetic polyesters and polyamides described above. In certain embodiments, blends of these polymer are combined with PLGA to form microparticles with differing environmental sensitivity and release properties; (a) the effect of microparticle (SP-6001) in CNV model mouse; (b) the effect of microparticle (SP-6001) in rhoNEGF (V6) mouse, 1 week after injection; and (c) the effect of microparticle (SP-6001) in rhoNEGF (V6) mouse, 8 weeks after injection.
REFERENCES
All publications, patent applications, patents, and other references mentioned in the specification are indicative of the level of those skilled in the art to which the presently disclosed subject matter pertains. All publications, patent applications, patents, and other references are herein incorporated by reference to the same extent as if each individual publication, patent application, patent, and other reference was specifically and individually indicated to be incorporated by reference. It will be understood that, although a number of patent applications, patents, and other references are referred to herein, such reference does not constitute an admission that any of these documents forms part of the common general knowledge in the art.
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Although the foregoing subject matter has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be understood by those skilled in the art that certain changes and modifications can be practiced within the scope of the appended claims.

## Claims

1. A microparticle comprising:




wherein:
n is an integer from 1 to 10,000;
R1 is absent;
R2, R3, R4, R5, R6, R7, R8, and R9 are each H;
R is selected from the group consisting of:




R′ is selected from the group consisting of:




R′′ is selected from the group consisting of:





and poly(lactide-co-glycolide) (PLGA); wherein the microparticle comprises an isolated peptide consisting of EIELVEEEPPF (SEQ ID NO: 2485).

2. The microparticle of claim 1, comprising a compound having the following structure: