Patent Publication Number: US-2010119483-A1

Title: Peptide viral entry inhibitors

Description:
This application is a divisional of U.S. patent application Ser. No. 11/264,509, filed Nov. 1, 2005 which claims the benefit of U.S. provisional patent application No. 60/624,204, filed Nov. 2, 2004; each of which is herein incorporated by reference in its entirety. 
    
    
     FIELD OF THE INVENTION 
     The present invention comprises compositions and methods for treating or preventing a viral infection in subject. 
     BACKGROUND OF THE INVENTION 
     Approximately 170 million people are infected with hepatitis C virus (HCV) world-wide. Current therapies are helpful, but are not effective in every patient. Moreover, many of the current therapies result in unwanted side-effects. 
     HCV particles attach and enter target cells through interactions between their viral glycoproteins E1 and E2 and cell surface receptor molecules. The viral entry step has been difficult to study because there is no reliable, easy to detect system for performing HCV/tissue culture infection. Hsu et al. (Proc. Natl. Acad. Sci. USA. 100(12):7271-7276 (2003)) and Bartosch et al. (J. Exp. Med. 197(5):633-42 (2003)) reported the generation of HCV pseudoparticles that use the core proteins of HIV-1 and authentic HCV E1 and E2 proteins. The pseudoparticles specifically infect hepatocytes and liver-derived cell lines. Such pseudoparticle infection can be neutralized by HCV patient serum as well as antibodies against E1 and E2 glycoproteins. CD81 is a host cell protein required, but not sufficient, for HCV pseudoparticle entry. 
     Peptides derived from HIV-1 envelope glycoproteins can bind HIV-1 and inhibit infection at the cell fusion step (Baldwin et al., Curr. Med. Chem. 10(17): 1633-1642 (2003)). Foung et al. (U.S. Pat. No. 6,692,908) discuss use of antibodies which inhibit HCV E1 and E1 binding to CD81 for treatment of HCV infection. Garry et al. (WO 2004/044220) discuss use of the peptides from the E1 envelope glycoprotein of hepaciviruses and E2 envelope glycoprotein of pestiviruses for treatment of viral infection. Furthermore, VanCompernolle et al. disclose imidazole-based small molecules that inhibit E2/CD81 binding (Virology 314(1):371-380 (2003)). 
     As mentioned above, in spite of the current availability of treatments for HCV, infections in many patients are not responsive. There remains a need in the art for additional treatments to the prevention and treatment of HCV infection. 
     SUMMARY OF THE INVENTION 
     The present invention, inter alia, meets the need in the art for additional therapies for the treatment and prevention of HCV infection. 
     The present invention provides an isolated polypeptide comprising or consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs: 3-139. In an embodiment of the invention, the polypeptide comprises or consists of the amino acid sequence of SEQ ID NO: 3, 7, 9, 10, 12-28, 30-38, 40, 42, 44-60, 62-68, 70, 71, 73-103, 106-120, 121-130, 132-138. 
     Another embodiment of the invention comprises an isolated polypeptide (i) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 82-84, 87-97, 99, 101-103 and 117-138; or (ii) consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs: 3-81, 85, 86, 98, 100, 104-116 and 139. A further embodiment of the invention comprises an isolated polypeptide (i) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 82-84, 87-97, 99, 101-103, 117-130 and 132-138; or (ii) consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs: 3, 7, 9, 10, 12-28, 30-38, 40, 42, 44-60, 62-68, 70-81, 85, 86, 98, 100 and 106-116. 
     Another embodiment of the invention comprises a pharmaceutical composition comprising an isolated polypeptide comprising or consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs: 3-139 and a pharmaceutically acceptable carrier. A further embodiment of the invention comprises a composition comprising an isolated polypeptide comprising or consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs: 3-139 in association with one or more members selected from the group consisting of anti-human CD81 antibody, ribavirin, interferon alfa-2a, interferon alfa-2b, interferon alfa-2c, interferon alfa n-1, interferon alfa n-3, consensus interferon, pegylated interferon alfa-2a, pegylated interferon alfa-2b, pegylated interferon alfa-2c, pegylated interferon alfa n-1, pegylated interferon alfa n-3, and pegylated consensus interferon (e.g., a kit). In an embodiment of the invention, an isolated peptide of the invention is combined in association with an HCV protease inhibitor or an HCV polymerase inhibitor. 
     The present invention also includes an oligonucleotide comprising the nucleotide sequence set forth in SEQ ID NO: 140 or 141. 
     The present invention also provides an isolated polynucleotide encoding a polypeptide comprising or consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs: 3-139. In an embodiment of the invention, the polynucleotide encodes a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 3, 7, 9, 10, 12-28, 30-38, 40, 42, 44-60, 62-68, 70, 71, 73-103, 106-120, 121-130 or 132-138. A further embodiment of the invention comprises a recombinant vector comprising an isolated polynucleotide encoding a polypeptide comprising or consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs: 3-139. Another embodiment of the invention comprises an isolated host cell comprising the vector. 
     The present invention also provides a method for making a polypeptide (e.g., any of SEQ ID NOs: 3-139) comprising culturing a host cell comprising a polynucleotide encoding the polypeptide under conditions in which the polynucleotide is expressed and, optionally, isolating the polypeptide from the culture. 
     The present invention also provides a method for inhibiting entry of a virus which is a member of the Flaviviridae family (e.g., hepatitis C virus) into a cell (e.g., in vitro or in vivo) comprising contacting the cell with a polypeptide comprising or consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs: 3-139. Also provided by the present invention is a method for treating or preventing infection of a subject with a virus which is a member of the Flaviviridae family comprising administering to said subject a therapeutically effective amount of a polypeptide of the present invention (e.g., any of SEQ ID NOs3-139). In an embodiment of the invention, the polypeptide (e.g., any of SEQ ID NOs: 3-139) is administered in association with one or more members selected from the group consisting of anti-human CD81 antibody, ribavirin, interferon alfa-2a, interferon alfa-2b, interferon alfa-2c, interferon alfa n-1, interferon alfa n-3, consensus interferon, pegylated interferon alfa-2a, pegylated interferon alfa-2b, pegylated interferon alfa-2c, pegylated interferon alfa n-1, pegylated interferon alfa n-3, and pegylated consensus interferon. In an embodiment of the invention, the pegylated interferon alfa that is administered is a pegylated interferon alfa-2b and wherein the amount of pegylated interferon alfa-2b that is administered in the treatment time period is about 0.5 to 1.5 micrograms per kilogram body weight of pegylated interferon alfa-2b protein per week on a weekly basis for at least twenty-four weeks (e.g., about 48 weeks). In an embodiment of the invention, said polypeptide (e.g., any of SEQ ID NOs: 3-139) is administered for a treatment time period sufficient to eradicate detectable hepatitis C virus-RNA and to maintain no detectable hepatitis C virus RNA for at least twelve weeks after the end of the treatment time period. In a further embodiment of the invention, said polypeptide (e.g., any of SEQ ID NOs: 3-139) is administered in association with a therapeutically effective amount of an interferon for a treatment time period sufficient to eradicate detectable hepatitis C virus-RNA and to maintain no detectable hepatitis C virus RNA for at least twelve weeks after the end of the treatment time period. In an embodiment of the invention, the host is infected with multiple hepatitis C virus genotypes (e.g., hepatitis C virus genotype 1 and/or hepatitis C virus genotype 2 and/or hepatitis C virus genotype 3). 
     The present invention also provides a method for preventing infection of a host, with a virus which is a member of the Flaviviridae family of viruses (e.g., hepatitis C virus), following transplantation of a liver into said host or transfusion of blood into said host comprising administering (e.g., parenterally (e.g., intramuscularly, intravenously, subcutaneously) or non-parenterally (e.g., orally)) to said host (e.g., before, during or after said transplantation or transfusion) a therapeutically effective amount of a polypeptide comprising or consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs: 3-139. In an embodiment of the invention, the polypeptide (e.g., any of SEQ ID NOs: 3-139) is administered in association with anti-human CD81 antibody, interferon-alfa, pegylated interferon-alfa or albumin-interferon-alpha (e.g., interferon alfa-2a, interferon alfa-2b, interferon alfa-2c, interferon alfa n-1, interferon alfa n-3, consensus interferon, pegylated interferon alfa-2a, pegylated interferon alfa-2b, pegylated interferon alfa-2c, pegylated interferon alfa n-1, pegylated interferon alfa n-3, or pegylated consensus interferon). In an embodiment of the invention, the polypeptide (e.g., any of SEQ ID NOs: 3-139) is administered in association with ribavirin. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     The present invention provides peptide compositions (e.g., any of SEQ ID NOs: 3-139) and methods for treating or preventing an infection by a virus which is a member of the Flaviviridae family (e.g., HCV) in a subject (e.g., a patient who has received a liver transplant) by administering one or more of the peptides to the subject. In an embodiment of the invention, the peptide comprises the amino acid sequence of any of SEQ ID NOs: 3, 7, 9, 10, 12-28, 30-38, 40, 42, 44-60, 62-68, 70, 71, 73-103, 106-120, 121-130, 132-138. 
     A patient or host suffering from an infection by a Flaviviridae virus, such as HCV (e.g., a chronic or acute HCV infection), can be treated by administering to the patient an E1-E2 polypeptide (e.g., any of SEQ ID NOs: 3-139) or a pharmaceutically acceptable salt thereof. 
     An E1-E2 peptide (e.g., comprising the amino acid sequence of any of SEQ ID NO: 3-139) can also be administered to a patient in association with one or more other anti-viral agents such as an anti-human CD81 antibody, pegylated or unpegylated interferon alfa-2a, pegylated or unpegylated interferon alfa-2b, pegylated or unpegylated interferon alfa-2c, pegylated or unpegylated interferon alfa n-1, pegylated or unpegylated interferon alfa n-3 or pegylated or unpegylated consensus interferon. 
     In a liver transplantation procedure, the donor liver can come from a living donor (i.e., living donor liver transplantation (LDLT)) wherein a portion of the donor&#39;s liver is removed and introduced into the recipient. Alternatively, the transplant can be from a deceased donor wherein the entire liver is removed and transplanted. 
     For example, the present invention includes, but is not limited to methods for treating or preventing infections caused by members of the Hepacivirus genus which includes the hepatitis C virus (HCV). HCV includes several types, subtypes and isolates: 
     hepatitis C virus (isolate 1) 
     hepatitis C virus (isolate BK) 
     hepatitis C virus (isolate EC1) 
     hepatitis C virus (isolate EC10) 
     hepatitis C virus (isolate HC-J2) 
     hepatitis C virus (isolate HC-J5) 
     hepatitis C virus (isolate HC-J6) 
     hepatitis C virus (isolate HC-J7) 
     hepatitis C virus (isolate HC-J8) 
     hepatitis C virus (isolate HC-JT) 
     hepatitis C virus (isolate HCT18) 
     hepatitis C virus (isolate HCT27) 
     hepatitis C virus (isolate HCV-476) 
     hepatitis C virus (isolate HCV-KF) 
     hepatitis C virus (isolate Hunan) 
     hepatitis C virus (isolate Japanese) 
     hepatitis C virus (isolate Taiwan) 
     hepatitis C virus (isolate TH) 
     hepatitis C virus isolate H 
     hepatitis C virus type 1
         hepatitis C virus type 1a
           hepatitis C virus strain H77   
           hepatitis C virus type 1b   hepatitis C virus type 1c   hepatitis C virus type 1d   hepatitis C virus type 1e   hepatitis C virus type 1f       

     hepatitis C virus type 10 
     hepatitis C virus type 2
         hepatitis C virus type 2a   hepatitis C virus type 2b   hepatitis C virus type 2c   hepatitis C virus type 2d   hepatitis C virus type 2f       

     hepatitis C virus type 3
         hepatitis C virus type 3a   hepatitis C virus type 3b   hepatitis C virus type 3g       

     hepatitis C virus type 4
         hepatitis C virus type 4a   hepatitis C virus type 4c   hepatitis C virus type 4d   hepatitis C virus type 4f   hepatitis C virus type 4h   hepatitis C virus type 4k       

     hepatitis C virus type 5
         hepatitis C virus type 5a       

     hepatitis C virus type 6
         hepatitis C virus type 6a       

     hepatitis C virus type 7
         hepatitis C virus type 7a   hepatitis C virus type 7b       

     hepatitis C virus type 8
         hepatitis C virus type 8a       

     The present invention also includes methods for treating or preventing infection caused by members of the  Flavivirus  genus. The  Flavivirus  genus includes Yellow fever virus; Tick-borne viruses such as the Gadgets Gully virus, Kadam virus, Kyasanur Forest disease virus, Langat virus, Omsk hemorrhagic fever virus, Powassan virus, Royal Farm virus, Karshi virus, Tick-borne encephalitis virus, Neudoerfl virus, Neudoerfl virus, Sofjin virus, Louping ill virus and the Negishi virus; seabird tick-borne viruses such as the Meaban virus, Saumarez Reef virus, and the Tyuleniy virus; mosquito-borne viruses such as the Aroa virus, Bussuquara virus, Iguape virus and the Naranjal virus; Dengue viruses such as the Dengue virus and the Kedougou virus; Japanese encephalitis viruses such as the Cacipacore virus, Koutango virus, Japanese encephalitis virus, Murray Valley encephalitis virus, Alfuy virus, St. Louis encephalitis virus, Usutu virus, West Nile virus, Kunjin virus and the Yaounde virus; Kokobera viruses such as the Kokobera virus and the Stratford virus; Ntaya viruses such as the Bagaza virus, Ilheus virus, Rocio virus, Israel turkey meningoencephalomyelitis virus, Ntaya virus and the Tembusu virus; Spondweni viruses such as the Zika virus and the Spondweni virus; Yellow fever viruses such as the Banzi virus, Bouboui virus, Edge Hill virus, Jugra virus, Saboya virus, Potiskum virus, Sepik virus, Uganda S virus, Wesselsbron virus and the Yellow fever virus; Entebbe viruses such as the Entebbe bat virus, Sokoluk virus, and the Yokose virus; Modoc viruses such as the Apoi virus, Cowbone Ridge virus, Jutiapa virus, Modoc virus, Sal Vieja virus and the San Perlita virus; Rio Bravo viruses such as the Bukalasa bat virus, Carey Island virus, Dakar bat virus, Montana myotis leukoencephalitis virus, Phnom Penh bat virus, Batu Cave virus, Rio Bravo virus, Tamana bat virus, and the Cell fusing agent virus. 
     The present invention also includes methods for treating or preventing infection caused by members of the  Pestivirus  genus. The  Pestivirus  genus includes Bovine viral diarrhea virus 1, Border disease virus (sheep), Bovine viral diarrhea virus 1, Bovine viral diarrhea virus 2, Classical swine fever virus, and Hog cholera virus. 
     Moreover, the present invention includes methods for treating or preventing infections caused by Hepatitis G virus or Hepatitis GB virus-A, B or C. 
     A “host”, “subject” or “patient” may be any organism, such as a mammal (e.g., primate, dog, cat, cow, horse, pig, goat, rat, mouse, bird), preferably a human. A host, subject or patient can be an organism, such as a human, that is co-infected with another virus such as the human immunodeficiency virus (HIV; e.g., HIV-1 or HIV-2). Accordingly, the present invention comprises methods and compositions for treating Flaviviridae infection in a host this also infected with HIV. 
     Molecular Biology 
     In accordance with the present invention there may be employed conventional molecular biology, microbiology, and recombinant DNA techniques within the skill of the art. Such techniques are explained fully in the literature. See, e.g., Sambrook, Fritsch &amp; Maniatis,  Molecular Cloning: A Laboratory Manual , Second Edition (1989) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (herein “Sambrook, et al., 1989”);  DNA Cloning: A Practical Approach , Volumes I and II (D. N. Glover ed. 1985);  Oligonucleotide Synthesis  (M. J. Gait ed. 1984);  Nucleic Acid Hybridization  (B. D. Hames &amp; S. J. Higgins eds. (1985));  Transcription And Translation  (B. D. Hames &amp; S. J. Higgins, eds. (1984));  Animal Cell Culture  (R. I. Freshney, ed. (1986));  Immobilized Cells And Enzymes  (IRL Press, (1986)); B. Perbal,  A Practical Guide To Molecular Cloning  (1984); F. M. Ausubel, et al. (eds.),  Current Protocols in Molecular Biology , John Wiley &amp; Sons, Inc. (1994). 
     The HCV E1 protein is well known in the art. For example, the an amino acid sequence of the HCV E1 protein is: 
     
       
         
           
               
            
               
                 (SEQ ID NO: 1) 
               
            
           
           
               
               
            
               
                   
                 yqvrnssgly hvtndcpnss ivyeaadail htpgcvpcvr 
               
               
                   
                   
               
               
                   
                 egnasrcwva vtptvatrdg klpttqlrrh idllvgsatl 
               
               
                   
                   
               
               
                   
                 csalyvgdlc gsvflvgqlf tfsprrhwtt qdcncsiypg 
               
               
                   
                   
               
               
                   
                 hitghrmawd mmmnwsptaa lvvaqllrip qaimdmiaga 
               
               
                   
                   
               
               
                   
                 hwgvlagiay fsmvgnwakv lvvlllfagv da 
               
            
           
         
       
     
     (see also Genbank accession no. NP 751920) 
     The HCV E2 protein is well known in the art. For example, the an amino acid sequence of the HCV E2 protein is: 
     
       
         
           
               
            
               
                 (SEQ ID NO: 2) 
               
            
           
           
               
               
            
               
                   
                 ethvtggsag rttaglvgll tpgakqniql intngswhin 
               
               
                   
                   
               
               
                   
                 stalncnesl ntgwlaglfy qhkfnssgcp erlascrrlt 
               
               
                   
                   
               
               
                   
                 dfaqgwgpis yangsglder pycwhypprp cgivpaksvc 
               
               
                   
                   
               
               
                   
                 gpvycftpsp vvvgttdrsg aptyswgand tdvfvlnntr 
               
               
                   
                   
               
               
                   
                 pplgnwfgct wmnstgftkv cgappcvigg vgnntllcpt 
               
               
                   
                   
               
               
                   
                 dcfrkhpeat ysrcgsgpwi tprcmvdypy rlwhypctin 
               
               
                   
                   
               
               
                   
                 ytifkvrmyv ggvehrleaa cnwtrgercd ledrdrsels 
               
               
                   
                   
               
               
                   
                 plllsttqwq vlpcsfttlp alstglihlh qnivdvqyly 
               
               
                   
                   
               
               
                   
                 gvgssiaswa ikweyvvllf llladarvcs clwmmllisq 
               
               
                   
                   
               
               
                   
                 aea 
               
            
           
         
       
     
     (see also Genbank accession nos. NP — 751921; AAB67038; AAB67036 and P27958). 
     The entire HCV genome is also disclosed, for example, under Genbank accession nos. AAB67038; NP — 671491; AAB67036; AAG02099; AAB67037; and AAP69952. 
     An example of a human CD81 is disclosed under Genbank accession no. NM004356. 
     A “polynucleotide”, “nucleic acid” or “nucleic acid molecule” includes the phosphate ester polymeric form of ribonucleosides (adenosine, guanosine, uridine or cytidine; “RNA molecules”) or deoxyribonucleosides (deoxyadenosine, deoxyguanosine, deoxythymidine, or deoxycytidine; “DNA molecules”), or any phosphoester analogs thereof, such as phosphorothioates and thioesters, in single stranded form, double-stranded form or otherwise. 
     A “polynucleotide sequence”, “nucleic acid sequence” or “nucleotide sequence” is a series of nucleotide bases (also called “nucleotides”) in a nucleic acid, such as DNA or RNA, and means any chain of two or more nucleotides. 
     A “coding sequence” or a sequence “encoding” an expression product, such as a RNA, polypeptide, protein, or enzyme, is a nucleotide sequence that, when expressed, results in production of the product. 
     The term “gene” means a DNA sequence that codes for or corresponds to a particular sequence of ribonucleotides or amino acids which comprise all or part of one or more RNA molecules, proteins or enzymes, and may or may not include regulatory DNA sequences, such as promoter sequences, which determine, for example, the conditions under which the gene is expressed. Genes may be transcribed from DNA to RNA which may or may not be translated into an amino acid sequence. 
     The present invention includes any nucleic acid fragment encoding a polypeptide taken from of any of SEQ ID NOs: 1 and 2. An embodiment of the invention includes any nucleic acid including at least about 24 (e.g., 25, 26, 27, 28, 29, 30, 31, 32, 33, 34), preferably at least about 35 (e.g., 25, 26, 27, 28, 29, 30, 31, 32, 33 or 34), more preferably at least about 45 (e.g., 35, 36, 37, 38, 39, 40, 41, 42, 43 or 44), and most preferably at least about 126 or more contiguous nucleotides (e.g., 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 150, 160, 170, 180, 190, 200, 300, 400, 500, 1000 or 1200) from any polynucleotide encoding a polypeptide of any of SEQ ID NOs: 1 or 2 (e.g., any of SEQ ID NOs: 3-139). 
     An embodiment of the invention includes any polynucleotide that encodes any of the polypeptides of the invention (e.g., any of SEQ ID NOs: 3-139), particularly any of SEQ ID NOs: 3, 7, 9, 10, 12-28, 30-38, 40, 42, 44-60, 62-68, 70, 71, 73-103, 106-120, 121-130, 132-138. 
     As used herein, the term “oligonucleotide” refers to a nucleic acid, generally of no more than about 100 nucleotides (e.g., 30, 40, 50, 60, 70, 80, or 90), that may be hybridizable to a genomic DNA molecule, a cDNA molecule, or an mRNA molecule encoding a gene, mRNA, cDNA, or other nucleic acid of interest. Oligonucleotides can be labeled, e.g., by incorporation of  32 P-nucleotides,  3 H-nucleotides,  14 C-nucleotides,  35 S-nucleotides or nucleotides to which a label, such as biotin, has been covalently conjugated. In one embodiment, a labeled oligonucleotide can be used as a probe to detect the presence of a nucleic acid. In another embodiment, oligonucleotides (one or both of which may be labeled) can be used as PCR primers, either for cloning full length or a fragment of the gene, or to detect the presence of nucleic acids. Generally, oligonucleotides are prepared synthetically, preferably on a nucleic acid synthesizer. 
     A “protein sequence”, “peptide sequence” or “polypeptide sequence” or “amino acid sequence” includes a series of two or more amino acids in a protein, peptide or polypeptide. 
     “Protein”, “peptide” or “polypeptide” includes a contiguous string of two or more amino acids. An embodiment of the invention includes any polypeptide comprising at least about 7 (e.g., 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19), more preferably at least about 20 (e.g., 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40), and yet more preferably at least about 42 (e.g., 43, 44, 45, 46, 47, 48, 49, 50, 60, 70, 80, 90, 100, 110, 120 or 130) or more contiguous amino acid residues from SEQ ID NOs: 1 or 2 (e.g., any of SEQ ID NOs: 3-139). 
     The scope of the present invention includes any of the polypeptides described herein (e.g., any of SEQ ID NOs: 3-139) comprising either D- or L-amino acids or one or more of either. For example, the present invention includes L-Val-L-Ser-L-Phe-L-Ala-L-Ile-L-Lys-L-Trp-L-Glu-L-Tyr-L-Val-L-Leu-L-Leu-L-Leu-L-Phe-L-Leu-L-Leu (SEQ ID NO: 77) as well as, for example, D-Val-D-Ser-D-Phe-D-Ala-D-Ile-D-Lys-D-Trp-D-Glu-D-Tyr-D-Val-D-Leu-D-Leu-D-Leu-D-Phe-D-Leu-D-Leu and L-Val-D-Ser-L-Phe-L-Ala-D-Ile-L-Lys-L-Trp-D-Glu-L-Tyr-L-Val-L-Leu-D-Leu-L-Leu-L-Phe-L-Leu-D-Leu. The present invention also includes any of the polypeptides described herein along with the reverse version of each peptide. For example, the present invention includes V-S-F-A-I-K-W-E-Y-V-L-L-L-F-L-L (SEQ ID NO: 77) along with the reverse of this peptide: L-L-F-L-L-L-V-Y-E-W-K-I-A-F-S-V. 
     The terms “isolated polynucleotide” or “isolated polypeptide” include a polynucleotide (e.g., RNA or DNA molecule, or a mixed polymer) or a polypeptide, respectively, which are partially or fully separated from other components that are normally found in cells or in recombinant DNA expression systems. These components include, but are not limited to, cell membranes, cell walls, ribosomes, polymerases, serum components and extraneous genomic sequences. 
     An isolated polynucleotide or polypeptide will, preferably, be an essentially homogeneous composition of molecules but may contain some heterogeneity. 
     “Amplification” of DNA as used herein includes the use of polymerase chain reaction (PCR) to increase the concentration of a particular DNA sequence within a mixture of DNA sequences. For a description of PCR see Saiki, et al., Science (1988) 239:487. 
     The term “host cell” includes any cell of any organism that is selected, modified, transfected, transformed, grown, or used or manipulated in any way, for the production of a substance by the cell, for example the expression or replication, by the cell, of a gene, a DNA or RNA sequence or a protein (e.g., chinese hamster ovary (CHO) cells and bacterial cells including  E. coli  (e.g., BL21, BL21DE3, DH5, DH5a and HB101 cells)). 
     The nucleotide sequence of a nucleic acid may be determined by any method known in the art (e.g., chemical sequencing or enzymatic sequencing). “Chemical sequencing” of DNA includes methods such as that of Maxam and Gilbert (1977) (Proc. Natl. Acad. Sci. USA 74:560), in which DNA is randomly cleaved using individual base-specific reactions. “Enzymatic sequencing” of DNA includes methods such as that of Sanger (Sanger, et al., (1977) Proc. Natl. Acad. Sci. USA 74:5463). 
     The nucleic acids herein may be flanked by natural regulatory (expression control) sequences, or may be associated with heterologous sequences, including promoters, internal ribosome entry sites (IRES) and other ribosome binding site sequences, enhancers, response elements, suppressors, signal sequences, polyadenylation sequences, introns, 5′- and 3′-non-coding regions, and the like. 
     In general, a “promoter” or “promoter sequence” is a DNA regulatory region capable of binding an RNA polymerase in a cell (e.g., directly or through other promoter-bound proteins or substances) and initiating transcription of a coding sequence. A promoter sequence is, in general, bounded at its 3′ terminus by the transcription initiation site and extends upstream (5′ direction) to include the minimum number of bases or elements necessary to initiate transcription at any level. Within the promoter sequence may be found a transcription initiation site (conveniently defined, for example, by mapping with nuclease S1), as well as protein binding domains (consensus sequences) responsible for the binding of RNA polymerase. The promoter may be operably associated with other expression control sequences, including enhancer and repressor sequences or with a nucleic acid of the invention. Promoters which may be used to control gene expression include, but are not limited to, cytomegalovirus (CMV) promoter (U.S. Pat. Nos. 5,385,839 and 5,168,062), the SV40 early promoter region (Benoist, et al., (1981) Nature 290:304-310), the promoter contained in the 3′ long terminal repeat of Rous sarcoma virus (Yamamoto, et al., (1980) Cell 22:787-797), the herpes thymidine kinase promoter (Wagner, et al., (1981) Proc. Natl. Acad. Sci. USA 78:1441-1445), the regulatory sequences of the metallothionein gene (Brinster, et al., (1982) Nature 296:39-42); prokaryotic promoters such as the β-lactamase promoter (VIIIa-Komaroff, et al., (1978) Proc. Natl. Acad. Sci. USA 75:3727-3731), or the tac promoter (DeBoer, et al., (1983) Proc. Natl. Acad. Sci. USA 80:21-25); see also “Useful proteins from recombinant bacteria” in Scientific American (1980) 242:74-94; and promoter elements from yeast or other fungi such as the Gal 4 promoter, the ADH (alcohol dehydrogenase) promoter, PGK (phosphoglycerol kinase) promoter or the alkaline phosphatase promoter. 
     A coding sequence is “under the control of”, “functionally associated with” or “operably associated with” a transcriptional and translational control sequence in a cell (e.g., a promoter), for example, when the sequence directs RNA polymerase mediated transcription of the coding sequence into RNA, preferably mRNA, which then may be RNA spliced (if it contains introns) and, optionally, translated into a protein encoded by the coding sequence. 
     The terms “express” and “expression” mean allowing or causing the information in a gene, RNA or DNA sequence to become manifest; for example, producing a protein by activating the cellular functions involved in transcription and translation of a corresponding gene. A DNA sequence is expressed in or by a cell to form an “expression product” such as an RNA (e.g., mRNA) or a protein. The expression product itself may also be said to be “expressed” by the cell. 
     The term “transformation” means the introduction of a nucleic acid into a cell. The introduced gene or sequence may be called a “clone”. A host cell that receives the introduced DNA or RNA has been “transformed” and is a “transformant” or a “clone.” The DNA or RNA introduced to a host cell can come from any source, including cells of the same genus or species as the host cell, or from cells of a different genus or species. The introduced nucleic acid can be maintained in the cell episomally or may be integrated into a chromosome of the cell. 
     The term “vector” includes a vehicle (e.g., a plasmid) by which a DNA or RNA sequence can be introduced into a host cell, so as to transform the host and, optionally, promote expression and/or replication of the introduced sequence. 
     Vectors that can be used in this invention include plasmids, viruses, bacteriophage, integratable DNA fragments, and other vehicles that may facilitate introduction of the nucleic acids into the genome of the host. Plasmids are the most commonly used form of vector but all other forms of vectors which serve a similar function and which are, or become, known in the art are suitable for use herein. See, e.g., Pouwels, et al.,  Cloning Vectors: A Laboratory Manual,  1985 and Supplements, Elsevier, N.Y., and Rodriguez et al. (eds.),  Vectors: A Survey of Molecular Cloning Vectors and Their Uses,  1988, Buttersworth, Boston, Mass. 
     The term “expression system” means a host cell and compatible vector which, under suitable conditions, can express a protein or nucleic acid which is carried by the vector and introduced to the host cell. Common expression systems include  E. coli  host cells and plasmid vectors, insect host cells and Baculovirus vectors, and mammalian host cells and vectors. 
     Expression of nucleic acids encoding the E1-E2 polypeptides of this invention (e.g., SEQ ID NOs: 3-139) can be carried out by conventional methods in either prokaryotic or eukaryotic cells. Although  E. coli  host cells are employed most frequently in prokaryotic systems, many other bacteria, such as various strains of  Pseudomonas  and  Bacillus , are known in the art and can be used as well. Suitable host cells for expressing nucleic acids encoding the E1-E2 polypeptides include prokaryotes and higher eukaryotes. Prokaryotes include both gram-negative and gram-positive organisms, e.g.,  E. coli  and  B. subtilis . Higher eukaryotes include established tissue culture cell lines from animal cells, both of non-mammalian origin, e.g., insect cells, and birds, and of mammalian origin, e.g., human, primates, and rodents. 
     Prokaryotic host-vector systems include a wide variety of vectors for many different species. A representative vector for amplifying DNA is pBR322 or many of its derivatives (e.g., pUC18 or 19). Vectors that can be used to express the E1-E2 polypeptides (e.g., SEQ ID NOs: 3-139) include, but are not limited to, those containing the lac promoter (pUC-series); trp promoter (pBR322-trp); lpp promoter (the pIN-series); lambda-pP or pR promoters (pOTS); or hybrid promoters such as ptac (pDR540). See Brosius et al., “Expression Vectors Employing Lambda-, trp-, lac-, and Ipp-derived Promoters”, in Rodriguez and Denhardt (eds.)  Vectors: A Surve of Molecular Clonin Vectors and Their Uses,  1988, Buttersworth, Boston, pp. 205-236. Many polypeptides can be expressed, at high levels, in an  E. coli /T7 bacteriophage expression system as disclosed in U.S. Pat. Nos. 4,952,496, 5,693,489 and 5,869,320 and in Davanloo, P., et al., (1984) Proc. Natl. Acad. Sci. USA 81: 2035-2039; Studier, F. W., et al., (1986) J. Mol. Biol. 189: 113-130; Rosenberg, A. H., et al., (1987) Gene 56: 125-135; and Dunn, J. J., et al., (1988) Gene 68: 259. 
     Higher eukaryotic tissue culture cells may also be used for the recombinant production of the E1-E2 polypeptides of the invention (e.g., SEQ ID NOs: 3-139). Although any higher eukaryotic tissue culture cell line might be used, including insect baculovirus expression systems, mammalian cells are preferred. Transformation or transfection and propagation of such cells have become a routine procedure. Examples of useful cell lines include HeLa cells, chinese hamster ovary (CHO) cell lines, J774 cells, Caco2 cells, baby rat kidney (BRK) cell lines, insect cell lines, bird cell lines, and monkey (COS) cell lines. Expression vectors for such cell lines usually include an origin of replication, a promoter, a translation initiation site. RNA splice sites (if genomic DNA is used), a polyadenylation site, and/or a transcription termination site. These vectors also, usually, contain a selection gene or amplification gene. Suitable expression vectors may be plasmids, viruses, or retroviruses carrying promoters derived, e.g., from such sources as adenovirus, SV40, parvoviruses, vaccinia virus, or cytomegalovirus. Examples of expression vectors include pCR®3.1, pcDNA1, pCD (Okayama, et al., (1985) Mol. Cell. Biol. 5:1136), pMC1neo Poly-A (Thomas, et al., (1987) Cell 51:503), pREP8, pSVSPORT and derivatives thereof, and baculovirus vectors such as pAC373 or pAC610. 
     The present invention also includes fusions which include any of the E1-E2 polypeptides (e.g., SEQ ID NOs: 3-139) and E1-E2 polynucleotides encoding said polypeptides of the present invention or a fragment thereof (discussed above) and a second polypeptide or polynucleotide moiety, which may be referred to as a “tag”. The fused polypeptides of the invention may be conveniently constructed, for example, by insertion of a polynucleotide of the invention or fragment thereof into an expression vector. The fusions of the invention may include tags which facilitate purification or detection. Such tags include glutathione-S-transferase (GST), hexahistidine (His6) tags, maltose binding protein (MBP) tags, haemagglutinin (HA) tags, cellulose binding protein (CBP) tags and myc tags. Detectable tags such as  32 P,  35 S,  3 H,  99m Tc,  123 I,  111 In,  68 Ga,  18 F,  125 I,  131 I,  113m In,  76 Br,  67 Ga,  99m Tc,  123 I,  111 In, and  68 Ga may also be used to label the polypeptides and polynucleotides of the invention. Methods for constructing and using such fusions are very conventional and well known in the art. 
     Modifications (e.g., post-translational modifications) that occur in a polypeptide often will be a function of how it is made. For polypeptides made by expressing a cloned gene in a host, for instance, the nature and extent of the modifications, in large part, will be determined by the host cell&#39;s post-translational modification capacity and the modification signals present in the polypeptide amino acid sequence. For instance, as is well known, glycosylation often does not occur in bacterial hosts such as  E. coli . Accordingly, when glycosylation is desired, a polypeptide can be expressed in a glycosylating host, generally a eukaryotic cell. Insect cells often carry out post-translational glycosylations which are similar to those of mammalian cells. For this reason, insect cell expression systems have been developed to express, efficiently, proteins having glycosylation. An insect cell which may be used in this invention is any cell derived from an organism of the class Insecta. For example, the insect can be  Spodoptera fruigiperda  (Sf9 or Sf21) or  Trichoplusia ni  (High 5). Examples of insect expression systems that can be used with the present invention, for example to produce E1-E2 polypeptide (e.g., SEQ ID NOs: 3-139), include Bac-To-Bac (Invitrogen Corporation, Carlsbad, Calif.) or Gateway (Invitrogen Corporation, Carlsbad, Calif.). If desired, deglycosylation enzymes can be used to remove carbohydrates attached during production in eukaryotic expression systems. 
     Other modifications may also include addition of aliphatic esters or amides to the polypeptide carboxyl terminus. The present invention also includes analogs of the E1-E2 polypeptides (e.g., SEQ ID NOs: 3-139) which contain modifications, such as incorporation of unnatural amino acid residues, or phosphorylated amino acid residues such as phosphotyrosine, phosphoserine or phosphothreonine residues. Other potential modifications include sulfonation, biotinylation, or the addition of other moieties. For example, the E1-E2 polypeptides of the invention (e.g., SEQ ID NOs: 3-139) may be appended with a polymer which increases the half-life of the peptide in the body of a subject. Polymers include polyethylene glycol (PEG) (e.g., PEG with a molecular weight of 2 kDa, 5 kDa, 10 kDa, 12 kDa, 20 kDa, 30 kDa and 40 kDa), dextran and monomethoxypolyethylene glycol (mPEG). 
     The peptides of the invention may also be cyclized. Specifically, the amino- and carboxy-terminal residues of an E1-E2 polypeptide (e.g., SEQ ID NOs: 3-139) or two internal residues of an E1-E2 polypeptide of the invention (e.g., SEQ ID NOs: 3-139) or a terminal and an internal residue of an E1-E3 polypeptide of the invention (e.g., SEQ ID NOs: 3-139) can be fused to create a cyclized peptide. Methods for cyclizing peptides are conventional and very well known in the art; for example see Gurrath, et al., (1992) Eur. J. Biochem. 210:911-921. 
     The present invention contemplates any superficial or slight modification to the amino acid or nucleotide sequences which correspond to the E1-E2 polypeptides of the invention (e.g., SEQ ID NOs: 3-139). In particular, the present invention contemplates sequence conservative variants of the nucleic acids which encode the polypeptides of the invention. “Sequence-conservative variants” of a polynucleotide sequence are those in which a change of one or more nucleotides in a given codon results in no alteration in the amino acid encoded at that position. Function-conservative variants of the polypeptides of the invention (e.g., any of SEQ ID NOs: 3-139) are also contemplated by the present invention along with nucleic acids encoding the variants. “Function-conservative variants” are those in which one or more amino acid residues in a protein or enzyme have been changed without significantly altering the overall conformation and/or function of the polypeptide, including, but, by no means, limited to, replacement of an amino acid with one having similar properties. Amino acids with similar properties are well known in the art. For example, polar/hydrophilic amino acids which may be interchangeable include asparagine, glutamine, serine, cysteine, threonine, lysine, arginine, histidine, aspartic acid and glutamic acid; nonpolar/hydrophobic amino acids which may be interchangeable include glycine, alanine, valine, leucine, isoleucine, proline, tyrosine, phenylalanine, tryptophan and methionine; acidic amino acids which may be interchangeable include aspartic acid and glutamic acid and basic amino acids which may be interchangeable include histidine, lysine and arginine. 
     The present invention includes E1-E2 polynucleotides (e.g., any polynucleotide encoding a polypeptide comprising an amino acid sequence selected from SEQ ID NOs: 3-139) and fragments thereof as well as nucleic acids which hybridize to the polynucleotides. Preferably, the nucleic acids hybridize under low stringency conditions, more preferably under moderate stringency conditions and most preferably under high stringency conditions. A nucleic acid molecule is “hybridizable” to another nucleic acid molecule, such as a cDNA, genomic DNA, or RNA, when a single stranded form of the nucleic acid molecule can anneal to the other nucleic acid molecule under the appropriate conditions of temperature and solution ionic strength (see Sambrook, et al., supra). The conditions of temperature and ionic strength determine the “stringency” of the hybridization. Typical low stringency hybridization conditions are 55° C., 5×SSC, 0.1% SDS, 0.25% milk, and no formamide at 42° C.; or 30% formamide, 5×SSC, 0.5% SDS at 42° C. Typical, moderate stringency hybridization conditions are similar to the low stringency conditions except the hybridization is carried out in 40% formamide, with 5× or 6×SSC at 42° C. High stringency hybridization conditions are similar to low stringency conditions except the hybridization conditions are carried out in 50% formamide, 5× or 6×SSC and, optionally, at a higher temperature (e.g., higher than 42° C.: 57° C., 59° C., 60° C., 62° C., 63° C., 65° C. or 68° C.). In general, SSC is 0.15M NaCl and 0.015M Na-citrate. Hybridization requires that the two nucleic acids contain complementary sequences, although, depending on the stringency of the hybridization, mismatches between bases are possible. The appropriate stringency for hybridizing nucleic acids depends on the length of the nucleic acids and the degree of complementation, variables well known in the art. The greater the degree of similarity or homology between two nucleotide sequences, the higher the stringency under which the nucleic acids may hybridize. For hybrids of greater than 100 nucleotides in length, equations for calculating the melting temperature have been derived (see Sambrook, et al., supra, 9.50-9.51). For hybridization with shorter nucleic acids, i.e., oligonucleotides, the position of mismatches becomes more important, and the length of the oligonucleotide determines its specificity (see Sambrook, et al., supra). 
     Also included in the present invention are polynucleotides comprising nucleotide sequences and polypeptides comprising amino acid sequences which are at least about 70% identical, preferably at least about 80% identical, more preferably at least about 90% identical and most preferably at least about 95% identical (e.g., 95%, 96%, 97%, 98%, 99%, 100%) to the reference E1-E2 nucleotide and amino acid sequences (e.g., SEQ ID NOs: 3-139) of the invention, when the comparison is performed by a BLAST algorithm wherein the parameters of the algorithm are selected to give the largest match between the respective sequences over the entire length of the respective reference sequences. Polypeptides comprising amino acid sequences which are at least about 70% similar, preferably at least about 80% similar, more preferably at least about 90% similar and most preferably at least about 95% similar (e.g., 95%, 96%, 97%, 98%, 99%, 100%) to the reference E1-E2 amino acid sequence of any of SEQ ID NOs: 3-139, when the comparison is performed with a BLAST algorithm wherein the parameters of the algorithm are selected to give the largest match between the respective sequences over the entire length of the respective reference sequences, are also included in the present invention. 
     Sequence identity refers to exact matches between the nucleotides or amino acids of two sequences which are being compared. Sequence similarity refers to both exact matches between the amino acids of two polypeptides which are being compared in addition to matches between nonidentical, biochemically related amino acids. Biochemically related amino acids which share similar properties and may be interchangeable are discussed above. 
     The following references regarding the BLAST algorithm are herein incorporated by reference: BLAST ALGORITHMS: Altschul, S. F., et al., (1990) J. Mol. Biol. 215:403-410; Gish, W., et al., (1993) Nature Genet. 3:266-272; Madden, T. L., et al., (1996) Meth. Enzymol. 266:131-141; Altschul, S. F., et al., (1997) Nucleic Acids Res. 25:3389-3402; Zhang, J., et al., (1997) Genome Res. 7:649-656; Wootton, J. C., et al., (1993) Comput. Chem. 17:149-163; Hancock, J. M., et al., (1994) Comput. Appl. Biosci. 10:67-70; ALIGNMENT SCORING SYSTEMS: Dayhoff, M. O., et al., “A model of evolutionary change in proteins.” in  Atlas of Protein Sequence and Structure , (1978) vol. 5, suppl. 3. M. O. Dayhoff (ed.), pp. 345-352, Natl. Biomed. Res. Found., Washington, D.C.; Schwartz, R. M., et al., “Matrices for detecting distant relationships.” in  Atlas of Protein Sequence and Structure , (1978) vol. 5, suppl. 3.” M. O. Dayhoff (ed.), pp. 353-358, Natl. Biomed. Res. Found., Washington, D.C.; Altschul, S. F., (1991) J. Mol. Biol. 219:555-565; States, D. J., et al., (1991) Methods 3:66-70; Henikoff, S., et al., (1992) Proc. Natl. Acad. Sci. USA 89:10915-10919; Altschul, S. F., et al., (1993) J. Mol. Evol. 36:290-300; ALIGNMENT STATISTICS: Karlin, S., et al., (1990) Proc. Natl. Acad. Sci. USA 87:2264-2268; Karlin, S., et al., (1993) Proc. Natl. Acad. Sci. USA 90:5873-5877; Dembo, A., et al., (1994) Ann. Prob. 22:2022-2039; and Altschul, S. F. “Evaluating the statistical significance of multiple distinct local alignments.” in  Theoretical and Computational Methods in Genome Research  (S. Suhai, ed.), (1997) pp. 1-14, Plenum, New York. 
     Protein Purification 
     The polypeptides of this invention (e.g., SEQ ID NOs: 3-139) can be purified by standard methods, including, but not limited to, salt or alcohol precipitation, affinity chromatography (e.g., used in conjunction with a purification tagged E1-E2 polypeptide as discussed above), preparative disc-gel electrophoresis, isoelectric focusing, high pressure liquid chromatography (HPLC), reversed-phase HPLC, gel filtration, cation and anion exchange and partition chromatography, and countercurrent distribution. Such purification methods are well known in the art and are disclosed, e.g., in “ Guide to Protein Purification”, Methods in Enzymology , Vol. 182, M. Deutscher, Ed., 1990, Academic Press, New York, N.Y. 
     Where an E1-E2 polypeptide (e.g., any of SEQ ID NOs: 3-139) is being isolated from a cellular or tissue source, it is preferable to include one or more inhibitors of proteolytic enzymes in the assay system, such as phenylmethanesulfonyl fluoride (PMSF), Pefabloc SC, pepstatin, leupeptin, chymostatin and EDTA. 
     Pharmaceutical Compositions 
     The present invention includes methods for using a pharmaceutical composition comprising a peptide of the present invention (e.g., any of SEQ ID NOs: 3-139) and a pharmaceutically acceptable carrier for treating a Flaviviridae infection. The pharmaceutical compositions may be prepared by any methods well known in the art of pharmacy; see, e.g., Gilman, et al., (eds.) (1990),  The Pharmacological Bases of Therapeutics,  8th Ed., Pergamon Press; A. Gennaro (ed.),  Remington&#39;s Pharmaceutical Sciences,  18th Edition, (1990), Mack Publishing Co., Easton, Pa.; Avis, et al., (eds.) (1993)  Pharmaceutical Dosage Forms Parenteral Medications  Dekker, New York; Lieberman, et al., (eds.) (1990)  Pharmaceutical Dosage Forms: Tablets  Dekker, New York; and Lieberman, et al., (eds.) (1990),  Pharmaceutical Dosage Forms: Disperse Systems  Dekker, New York. 
     A pharmaceutical composition containing an E1-E2 peptide of the present invention (e.g., any of SEQ ID NOs: 3-139) can be prepared using conventional pharmaceutically acceptable excipients and additives and conventional techniques. Such pharmaceutically acceptable excipients and additives include non-toxic compatible fillers, binders, disintegrants, buffers, preservatives, anti-oxidants, lubricants, flavorings, thickeners, coloring agents, emulsifiers and the like. All routes of administration are contemplated including, but not limited to, parenteral (e.g., subcutaneous, intravenous, intraperitoneal, intramuscular) and non-parenteral (e.g., oral, transdermal, intranasal, intraocular, sublingual, inhalation, rectal and topical). 
     Unit forms of administration include oral forms such as tablets, capsules, powders, cachets, granules and solutions or suspensions, sublingual and buccal forms of administration, aerosols, implants, subcutaneous, intramuscular, intravenous, intranasal, intraocular, subcutaneous or rectal forms of administration. 
     When a solid composition is prepared in the form of tablets, e.g., a wetting agent such as sodium lauryl sulfate can be added to micronized or non-micronized compounds and mixed with a pharmaceutical vehicle such as silica, gelatin starch, lactose, magnesium stearate, talc, gum arabic or the like. The tablets can be coated with sucrose, various polymers, or other appropriate substances. Tablets can be treated so as to have a prolonged or delayed activity and so as to release a predetermined amount of active principle continuously or at predetermined intervals, e.g., by using ionic resins and the like. 
     A preparation in the form of gelatin capsules may be obtained, e.g., by mixing an E1-E2 peptide of the present invention (e.g., any of SEQ ID NOs: 3-139) with a diluent, such as a glycol or a glycerol ester, and incorporating the resulting mixture into soft or hard gelatin capsules. 
     A preparation in the form of a syrup or elixir can contain an E1-E2 peptide of the present invention (e.g., any of SEQ ID NOs: 3-139), e.g., with a sweetener, methylparaben and propylparaben as antiseptics, flavoring agents and an appropriate color. 
     Water-dispersible powders or granules can contain an E1-E2 peptide of the present invention (e.g., any of SEQ ID NOs: 3-139) mixed, e.g., with dispersants, wetting agents or suspending agents, such as polyvinylpyrrolidone, as well as with sweeteners and/or other flavoring agents. 
     Rectal administration may be provided by using suppositories which may be prepared, e.g., with binders melting at the rectal temperature, for example cocoa butter or polyethylene glycols. 
     Parenteral, intranasal or intraocular administration may be provided by using, e.g., aqueous suspensions, isotonic saline solutions or sterile and injectable solutions containing pharmacologically compatible dispersants and/or solubilizers, for example, propylene glycol or polyethylene glycol. 
     Thus, to prepare an aqueous solution for intravenous injection, it is possible to use a co-solvent, e.g., an alcohol such as ethanol or a glycol such as polyethylene glycol or propylene glycol, and a hydrophilic surfactant such as Tween® 80. An oily solution injectable intramuscularly can be prepared, e.g., by solubilizing the active principle with a triglyceride or a glycerol ester. 
     Transdermal administration can be provided by using patches in the form of a multilaminate, or with a reservoir, containing an a peptide of the present invention (e.g., any of SEQ ID NOs: 3-139) and an appropriate solvent. 
     Administration by inhalation can be provided by using, e.g., an aerosol containing sorbitan trioleate or oleic acid, for example, together with trichlorofluoromethane, dichlorofluoromethane, dichlorotetrafluoroethane or any other biologically compatible propellant gas; it is also possible to use a system containing an E1-E2 peptide of the present invention (e.g., any of SEQ ID NOs: 3-139), by itself or associated with an excipient, in powder form. 
     An E1-E2 peptide of the present invention (e.g., any of SEQ ID NOs: 3-139) can also be formulated as microcapsules or microspheres, e.g., liposomes, optionally with one or more carriers or additives. 
     Implants are among the prolonged release forms which can be used in the case of chronic treatments. They can be prepared in the form of an oily suspension or in the form of a suspension of microspheres in an isotonic medium. 
     Methods of the present invention can include administration of an E1-E2 peptide of the present invention (e.g., any of SEQ ID NOs: 3-139) in association with, for example, one or more known anti-viral agents. The administration and dosage of such agents is typically as according to the schedule listed in the product information sheet of the approved agents, in the  Physicians&#39; Desk Reference  2003 ( Physicians&#39; Desk Reference,  57th Ed); Medical Economics Company; ISBN: 1563634457; 57th edition (November 2002), as well as therapeutic protocols well known in the art. 
     Suitable anti-viral agents, with which a peptide of the invention (e.g., any of SEQ ID NOs: 3-139) can be administered or mixed or formulated include, but are not limited to, pegylated or unpegylated interferon alfa-2a, pegylated or unpegylated interferon alfa-2b, pegylated or unpegylated interferon alfa-2c, pegylated or unpegylated interferon alfa n-1, pegylated or unpegylated interferon alfa n-3 and pegylated, unpegylated consensus interferon or albumin-interferon-alpha. 
     The term “interferon alpha” as used herein means the family of highly homologous species-specific proteins that inhibit viral replication and cellular proliferation and modulate immune response. Typical suitable interferon-alphas include, but are not limited to, recombinant interferon alpha-2b, recombinant interferon alpha-2a, recombinant interferon alpha-2c, alpha 2 interferon, interferon alpha-n1 (INS), a purified blend of natural alpha interferons, a consensus alpha interferon such as those described in U.S. Pat. Nos. 4,897,471 and 4,695,623 (especially Examples 7, 8 or 9 thereof), or interferon alpha-n3, a mixture of natural alpha interferons. 
     Interferon alfa-2a is sold as ROFERON-A® by Hoffmann-La Roche (Nutley, N.J.). 
     Interferon alfa-2b is sold as INTRON-A® by Schering Corporation (Kenilworth, N.J.). Interferon alfa-2b is also sold, in combination with ribavirin, as REBETRON® by Schering Corporation (Kenilworth, N.J.). The manufacture of interferon alpha 2b is described, for example, in U.S. Pat. No. 4,530,901. 
     Interferon alfa-n3 is a mixture of natural interferons sold as ALFERON N INJECTION® by Hemispherx Biopharma, Inc. (Philadelphia, Pa.). 
     Interferon alfa-n1 (INS) is a mixture of natural interferons sold as WELLFERON® by Glaxo-Smith-Kline (Research Triangle Park, N.C.). 
     Consensus interferon is sold as INFERGEN® by Intermune, Inc. (Brisbane, Calif.). 
     Interferon alfa-2c is sold as BEROFOR® by Boehringer Ingelheim Pharmaceutical, Inc. (Ridgefield, Conn.). 
     A purified blend of natural interferons is sold as SUMIFERON® by Sumitomo; Tokyo, Japan. 
     A multi-subtype natural interferon derived from human white blood cells is sold by Viragen, Inc (Plantation, Fla.), as Omniferon™. Viragen, Inc. also sells a highly purified, multi-subtype, natural human alpha interferon derived from human white blood cells, as Multiferon™. (U.S. Pat. No. 6,743,624). 
     Pegylated interferon alpha may also be administered in association with an E1-E2 peptide of the present invention (e.g., any of SEQ ID NOs: 3-139). The term “pegylated interferon alpha” as used herein means polyethylene glycol modified conjugates of interferon alpha, preferably interferon alpha-2a and alpha-2b. The preferred polyethylene-glycol-interferon alpha-2b conjugate is PEG 12000-interferon alpha-2b. The phrases “12,000 molecular weight polyethylene glycol conjugated interferon alpha” and “PEG 12000-IFN alpha” as used herein include conjugates such as are prepared according to the methods of International Application No. WO 95/13090 and containing urethane linkages between the interferon alpha-2a or -2b amino groups and polyethylene glycol having an average molecular weight of 12000. The pegylated inteferon alpha, PEG 12000-IFN-alpha-2b is available from Schering-Plough Research Institute, Kenilworth, N.J. 
     The preferred PEG 12000-interferon alpha-2b can be prepared by attaching a PEG polymer to the epsilon amino group of a lysine residue in the interferon alpha-2b molecule. A single PEG 12000 molecule can be conjugated to free amino groups on an IFN alpha-2b molecule via a urethane linkage. This conjugate is characterized by the molecular weight of PEG 12000 attached. The PEG 12000-IFN alpha-2b conjugate can be formulated as a lyophilized powder for injection. 
     Pegylated interferon alfa-2b is sold as PEG-INTRON® by Schering Corporation (Kenilworth, N.J.). 
     Pegylated interferon-alfa-2a is sold as PEGASYS® by Hoffmann-La Roche (Nutley, N.J.). 
     Other interferon alpha conjugates can be prepared by coupling an interferon alpha to a water-soluble polymer. A non-limiting list of such polymers include other polyalkylene oxide homopolymers such as polypropylene glycols, polyoxyethylenated polyols, copolymers thereof and block copolymers thereof. As an alternative to polyalkylene oxide-based polymers, effectively non-antigenic materials such as dextran, polyvinylpyrrolidones, polyacrylamides, polyvinyl alcohols, carbohydrate-based polymers and the like can be used. Such interferon alpha-polymer conjugates are described, for example, in U.S. Pat. No. 4,766,106, U.S. Pat. No. 4,917,888, European Patent Application No. 0 236 987 or 0 593 868 or International Publication No. WO 95/13090. 
     Pharmaceutical compositions of pegylated interferon alpha suitable for parenteral administration can be formulated with a suitable buffer, e.g., Tris-HCl, acetate or phosphate such as dibasic sodium phosphate/monobasic sodium phosphate buffer, and pharmaceutically acceptable excipients (e.g., sucrose), carriers (e.g. human plasma albumin), toxicity agents (e.g., NaCl), preservatives (e.g., thimerosol, cresol or benzyl alcohol), and surfactants (e.g., tween or polysorbates) in sterile water for injection. The pegylated interferon alpha can be stored as lyophilized powders under refrigeration at 2°-8° C. The reconstituted aqueous solutions are stable when stored between 2° and 8° C. and used within 24 hours of reconstitution. See for example U.S. Pat. Nos. 4,492,537; 5,762,923 and 5,766,582. The reconstituted aqueous solutions may also be stored in pre-filled, multi-dose syringes such as those useful for delivery of drugs such as insulin. Typical, suitable syringes include systems comprising a prefilled vial attached to a pen-type syringe such as the NOVOLET® Novo Pen available from Novo Nordisk or the REDIPEN®, available from Schering Corporation, Kenilworth, N.J. Other syringe systems include a pen-type syringe comprising a glass cartridge containing a diluent and lyophilized pegylated interferon alpha powder in a separate compartment. 
     In an embodiment of the invention, one or more other anti-viral substances may be administered with one or more E1-E2 peptides of the present invention (e.g., any of SEQ ID NOs: 3-139). 
     Other types of compounds which may be administered with an E1-E2 peptide of the present invention (e.g., any of SEQ ID NOs: 3-139) include, but are not limited to, ribonucleoside analogues, IMPDH inhibitors, N-glycosylation inhibitors, N3 protease inhibitors, NS5B inhibitors, immunomodulatory compounds and CTP synthase inhibitors, thiazolidine derivatives, benzanilides, phenanthrenequinones, helicase inhibitors, polymerase inhibitors, antisense phosphothioate oligodeoxynucleotides, IRES-dependent translation inhibitors, nuclease resistant ribozymes, 1-amino-alkyloyclohexanes, alkyl lipids, antioxidants, squalene, amantadine, bile acids, N-(phosphonoacetyl)-L-aspartic acid, benzenedicarboxamides, polyadenylic acid derivatives, 2′,3′ dideoxyinosine and benzimidazoles. 
     In an embodiment of the present invention, ribavirin 
     
       
         
         
             
             
         
       
     
     is administered in association with an E1-E2 peptide of the present invention (e.g., any of SEQ ID NOs: 3-139). Ribavirin is sold as REBETOL® by Schering Corporation; Kenilworth, N.J. Its manufacture and formulation is described, for example, in U.S. Pat. No. 4,211,771. A combination of ribavirin and recombinant interferon alfa-2b (REBETRON®; Schering Corporation; Kenilworth, N.J.) may also be administered in association with an E1-E2 peptide of the present invention (e.g., any of SEQ ID NOs: 3-139). 
     In another embodiment of the invention, gemcitabine 
     
       
         
         
             
             
         
       
     
     is administered in association with an E1-E2 peptide of the present invention (e.g., any of SEQ ID NOs: 3-139). Gemcitabine is sold as GEMZAR® by Eli Lilly and Co. (Indianapolis, Ind.). 
     A further embodiment of the present invention comprises administering an E1-E2 peptide of the present invention (e.g., any of SEQ ID NOs: 3-139) in association with VX497 
     
       
         
         
             
             
         
       
     
     An embodiment of the invention comprises administering mycophenolate mofetil (MMF; 2-morpholinoethyl (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoate) in association with an E1-E2 peptide of the present invention (e.g., any of SEQ ID NOs: 3-139). MMF is sold as CellCept® by Roche Laboratories; Nutley, N.J. 
     Another embodiment comprises administerina EICAR 
     
       
         
         
             
             
         
       
     
     in association with an E1-E2 peptide of the present invention (e.g., any of SEQ ID NOs: 3-139). 
     An embodiment of the present invention comprises administering tiazofurin 
     
       
         
         
             
             
         
       
     
     in association with an E1-E2 peptide of the present invention (e.g., any of SEQ ID NOs: 3-139). 
     Another embodiment of the invention comprises administering deoxynojirimycin and/or derivatives thereof, such as N-nonyl-deoxynojirimycin (De Clercq et al., Mini Rev Med. Chem. 2(2):163-75 (2002)) or n-butyl deoxynojirimycin (nB-DNJ; Ouzounov et al., Antiviral Res. 55(3):425-35 (2002)), in association with an E1-E2 peptide of the present invention (e.g., any of SEQ ID NOs: 3-139). 
     Another embodiment of the invention comprises administering colchicine 
     
       
         
         
             
             
         
       
     
     in association with an E1-E2 peptide of the invention (e.g., any of SEQ ID NOs: 3-139). 
     In one embodiment, an E1-E2 peptide of the present invention (e.g., any of SEQ ID NOs: 3-139) is administered in association with albumin-interferon alpha (ALBUFERON™). Albumin-interferon alpha is interferon-α fused to human serum albumin. ALBUFERON™ is available from Human Genome Sciences, Rockville, Md. ALBUFERON™ has been shown to be effective for treatment of hepatitis C virus infections (Blaire et al., J. Pharm and Exp. Therap. 303(2): 540-548 (2002)). 
     In another embodiment, BILN-2061 
     
       
         
         
             
             
         
       
     
     is administered in association with an E1-E2 peptide of the present invention (e.g., any of SEQ ID NOs: 3-139). 
     In another embodiment, thymalfasin (e.g., ZADAXIN™) is administered in association with an E1-E2 peptide of the present invention (e.g., any of SEQ ID NOs: 3-139). ZADAXIN™ is available from SciClone Pharmaceuticals International, Ltd., San Mateo, Calif. 
     In yet another embodiment, isatoribine 
     
       
         
         
             
             
         
       
     
     is administered in association with an E1-E2 peptide of the present invention (e.g., any of SEQ ID NOs: 3-139). 
     In another embodiment, an E1-E2 peptide of the invention (e.g., any of SEQ ID NOs: 3-139) is administered in association with an NS5B inhibitor such as NM283 or NM107 (Idenix Pharmaceuticals; Cambridge, Mass.). 
     In another embodiment, an E1-E2 peptide of the present invention (e.g., any of SEQ ID NOs: 3-139) is administered in association with SCH68631 
     
       
         
         
             
             
         
       
     
     or SCH351633 
     
       
         
         
             
             
         
       
     
     In a further embodiment, an E1-E2 peptide of the present invention (e.g., any of SEQ ID NOs: 3-139) is administered in association with any of the P 1  variants of Elgin c disclosed in Qasim et al., Biochemistry 36: 1598-1607 (1997). 
     In yet another embodiment, an E1-E2 peptide of the present invention (e.g., any of SEQ ID NOs: 3-139) is administered in association with gliotoxin 
     
       
         
         
             
             
         
       
     
     Other embodiments of the invention include administering an E1-E2 peptide of the present invention (e.g., any of SEQ ID NOs: 3-139) in association 
     with RD3-4082 
     
       
         
         
             
             
         
       
     
     or with RD3-4078 
     
       
         
         
             
             
         
       
     
     or any other protease inhibitor disclosed in Sudo et al. 
     A further embodiment of the invention comprises administering an E1-E2 peptide of the present invention (e.g., any of SEQ ID NOs: 3-139) in association with 
     
       
         
         
             
             
         
       
     
     Kakiuchi et al., FEBS Letters 421: 217-220 (1998)) or any other proteinase inhibitor disclosed in Kakiuchi et al. 
     A further embodiment of the invention comprises administering an E1-E2 peptide of the present invention (e.g., any of SEQ ID NOs: 3-139) in association with helioxanthin 
     
       
         
         
             
             
         
       
     
     A further embodiment of the invention comprises administering an E1-E2 peptide of the present invention (e.g., any of SEQ ID NOs: 3-139) in association with HE2000 
     
       
         
         
             
             
         
       
     
     Another embodiment of the present invention comprises administering an E1-E2 peptide of the present invention (e.g., any of SEQ ID NOs: 3-139) in association with RD4-6205 
     
       
         
         
             
             
         
       
     
     or any other protease inhibitor disclosed in Sudo et al. 
     An embodiment of the present invention comprises administering an E1-E2 peptide of the present invention (e.g., any of SEQ ID NOs: 3-139) in association with cerulenin 
     
       
         
         
             
             
         
       
     
     or any other HCV RNA-dependent RNA polymerase (RdRp) inhibitor disclosed in Lohmann et al. 
     An embodiment of the present invention comprises administering an E1-E2 peptide of the present invention (e.g., any of SEQ ID NOs: 3-139) in association with ceplene 
     
       
         
         
             
             
         
       
     
     An additional embodiment of the present invention comprises administering an E1-E2 peptide of the present invention (e.g., any of SEQ ID NOs: 3-139) in association with 
     
       
         
         
             
             
         
       
     
     (DiMarco et al., J. Biol. Chem., Vol. 275 (10): 7152-71572000); 
     
       
         
         
             
             
         
       
     
     (Barbato et al., EMBO J. 19: 1195-1206 (2000)) or any of the NS3/4a protease inhibitors disclosed by Ingallinella et al., Biochemistry, 41(17): 5483-5492 (2002). 
     Yet another embodiment of the present invention comprises administering an E1-E2 peptide of the present invention (e.g., any of SEQ ID NOs: 3-139) in association with amantadine 
     
       
         
         
             
             
         
       
     
     A further embodiment of the present invention comprises administering an E1-E2 peptide of the present invention (e.g., any of SEQ ID NOs: 3-139) in association with IDN-6556 
     
       
         
         
             
             
         
       
     
     A further embodiment of the present invention comprises administering an E1-E2 peptide of the present invention (e.g., any of SEQ ID NOs: 3-139) in association with beta-Alethine (beta-alanyl-cysteamine disulfide). 
     Yet another embodiment of the present invention comprises administering an E1-E2 peptide of the present invention (e.g., any of SEQ ID NOs: 3-139) in association with naphthoquinone, 2-methylnaphthoquinone, 2-hydroxynaphthoquinone, 5-hydroxynaphthoquinone, 5,8-dihydroxynaphthoquinone, alkannin or shikonin (Takeshita et al., Analytical Biochem. 247: 242-246 (1997)). 
     A further embodiment of the present invention comprises administering an E1-E2 peptide of the present invention (e.g., any of SEQ ID NOs: 3-139) in association with 1-amino-1,3,5-trimethylcyclohexane, 1-amino-1(trans),3(trans),5-trimethylcyclohexane, 1-amino-1(cis),3(cis),5-trimethylcyclohexane, 1-amino-1,3,3,5-tetramethylcyclohexane, 1-amino-1,3,3,5,5-pentamethylcyclohexane, 1-amino-1,3,5,5-tetramethyl-3-ethylcyclohexane, 1-amino-1,5,5-trimethyl-3,3-diethylcyclohexane, 1-amino-1,5,5-trimethyl-cis-3-ethylcyclohexane, 1-amino-(1S,5S)cis-3-ethyl-1,5,5-trimethylcyclohexane, 1-amino-1,5,5-trimethyl-trans-3-ethylcyclohexane, 1-amino-(1R,5S)trans-3-ethyl-1,5,5-trimethylcyclohexane, 1-amino-1-ethyl-3,3,5,5-tetramethylcyclohexane, 1-amino-1-propyl-3,3,5,5-tetramethylcyclohexane, N-methyl-1-amino-1,3,3,5,5-pentamethylcyclohexane, N-ethyl-1-amino-1,3,3,5,5-pentamethylcyclohexane, or N-(1,3,3,5,5-pentamethylcyclohexyl) pyrrolidine or any other 1-aminoalkylcyclohexane N-methyl-D-aspartate (NMDA) inhibitors disclosed in U.S. Pat. No. 6,034,134. 
     A further embodiment of the present invention comprises administering an E1-E2 peptide of the present invention (e.g., any of SEQ ID NOs: 3-139) in association with d-α-tocopherol or any other anti-HCV compound disclosed in U.S. Pat. No. 5,922,757. 
     Another embodiment of the present invention comprises administering an E1-E2 peptide of the present invention (e.g., any of SEQ ID NOs: 3-139) in association with tauroursodeoxycholic acid, chenodeoxycholic acid, ursodeoxycholic acid 
     
       
         
         
             
             
         
       
     
     or free bile acid or any other bile acid HCV inhibitor disclosed in U.S. Pat. No. 5,846,964. 
     A further embodiment of the present invention comprises administering an E1-E2 peptide of the present invention (e.g., any of SEQ ID NOs: 3-139) in association with interleukin 23 (IL-23) or IL-27 (Matsui et al., J. Virol. 78(17):9093-104 (2004)). 
     Another embodiment of the present invention comprises administering an E1-E2 peptide of the present invention (e.g., any of SEQ ID NOs: 3-139) in association with 1,1′-[1,4-phenylenebis (methylene)]bis(4,4′-trans-(4,5,6,7,8,9-hexahydro) benzimidazoyl)piperidine, 1,1′-[1,4-phenylenebis(methylene)]bis(4,4′-benzimidazoyl) piperidine or any other anti-HCV compound disclosed in U.S. Pat. No. 5,830,905. 
     Another embodiment of the present invention comprises administering an E1-E2 peptide of the present invention (e.g., any of SEQ ID NOs: 3-139) in association with N,N′-4-[(2-benzimidazole)phenyl]-1,4-butenedicarboxamide, N,N′-4-[(2-benzimidazole)phenyl]-1,6-hexanedicarboxamide, N,N′-4-[(2-benzimidazole)phenyl]-1,8-octanedicarboxamide, N,N′-4-[(2-benzimidazole)phenyl]-1,9-nonanedicarboxamide, N,N′-4-[(2-benzimidazole)phenyl]-1,10-decanedicarboxamide or N,N′-4-[(2-benzimidazole)phenyl]-1,4-butenedicarboxamide or any other carboxamide HCV inhibitor disclosed in U.S. Pat. No. 5,633,388. 
     Another embodiment of the present invention comprises administering an E1-E2 peptide of the present invention (e.g., any of SEQ ID NOs: 3-139) in association with any of the polyadenylic acid (5′) derivatives disclosed in U.S. Pat. No. 5,496,546. 
     A further embodiment of the present invention comprises administering an E1-E2 peptide of the present invention (e.g., any of SEQ ID NOs: 3-139) in association with 2′,3′-dideoxyinosine (U.S. Pat. No. 5,026,687). 
     An embodiment of the present invention comprises administering an E1-E2 peptide of the present invention (e.g., any of SEQ ID NOs: 3-139) in association with 
     
       
         
         
             
             
         
       
     
     or any other benzimidazole disclosed in U.S. Pat. No. 5,891,874. 
     An additional embodiment of the invention comprises administering VX-950 
     
       
         
         
             
             
         
       
     
     in association with an E1-E2 peptide of the present invention (e.g., any of SEQ ID NOs: 3-139). 
     Another embodiment of the present invention comprises administering an E1-E2 peptide of the present invention (e.g., any of SEQ ID NOs: 3-139) in association with viramidine 
     
       
         
         
             
             
         
       
     
     or levovirin 
     
       
         
         
             
             
         
       
     
     A further embodiment of the invention includes administering an E1-E2 peptide of the invention (e.g., any of SEQ ID NOs: 3-139) in association with IDB-1016 (4H-1-Benzopyran-4-one, 2-(2,3-dihydro-3-(4-hydroxy-3-methoxyphenyl)-2-(hydroxymethyl)-1,4-benzodioxin-6-yl)-2,3-dihydro-3,5,7-trihydroxy-, (2R-(2alpha,3beta,6(2R*,3R*)))-, mixt. with soya phosphatidylcholines; CAS No. 134499-06-2). 
     Another embodiment of the present invention comprises administering an E1-E2 peptide of the present invention (e.g., any of SEQ ID NOs: 3-139) in association with the anti-sense polynucleotide ISIS-14803 (d(P-thio)(G-T-G-m5C-T-m5C-A-T-G-G-T-G-m5C-A-m5C-G-G-T-m5C-T) DNA). 
     Yet another embodiment of the present invention comprises administering an E1-E2 peptide of the present invention (e.g., any of SEQ ID NOs: 3-139) in association with any of the E2/CD81 binding inhibitors disclosed in VanCompernolle et al. (Virology 314: 371-380 (2003)), particularly compound 5 or 7 therein. 
     Moreover, in an embodiment of the invention, an E1-E2 peptide of the invention (e.g., any of SEQ ID NOs: 3-139) is administered in association with an anti-CD81 antibody (e.g., an anti-human CD81 antibody). Anti-CD81 antibodies are available commercially from several sources and can be made by any practitioner of ordinary skill in the art using conventionally known techniques. For example, BD Biosciences (San Jose, Calif.) sells an anti-human CD81 antibody (see also Oren, et al., Mol. Cell. Biol. 10: 4007 (1990); Bradbury, et al., J. Immunol. 149: 2841 (1992) or Schick, et al., J. Immunol. 151:4090 (1993)). The present invention includes embodiments wherein an E1-E2 peptide of the invention (e.g., any of SEQ ID NOs: 3-139) is administered in association with an anti-human CD81 antibody or a fragment thereof, preferably an antigen-binding fragment, thereof; including monoclonal antibodies, polyclonal antibodies, bispecific antibodies, Fab antibody fragments, F(ab) 2  antibody fragments, Fv antibody fragments (e.g., VH or VL), single chain Fv antibody fragments and dsFv antibody fragments. Furthermore, the antibodies of the invention may be fully human antibodies or chimeric antibodies. Preferably, the anti-CD81 antibody is a monoclonal, fully human antibody. 
     Combinations of the invention include an E1-E2 peptide of the present invention (e.g., any of SEQ ID NOs: 3-139) “in association” with one or more (e.g., 2, 3, 4, 5) additional anti-viral agents (e.g., ribavirin, interferon alfa-2a or 2b, or pegylated interferon alfa-2a or 2b). The term “in association” indicates that the components of the combinations of the invention can be formulated into a single composition for simultaneous delivery or formulated separately into two or more compositions (e.g., a kit). Furthermore, each component of a combination of the invention can be administered to a subject at a different time than when the other component is administered; for example, each administration may be given non-simultaneously (e.g., separately or sequentially) at several intervals over a given period of time. Moreover, the separate components may be administered to a subject by the same or by a different route (e.g., orally, intravenously, subcutaneously). 
     The present invention further comprises compositions comprising an E1-E2 peptide of the present invention (e.g., SEQ ID NOs: 3-139) in combination or in association with one or more anti-viral agents discussed above (e.g., pegylated interferon alfa-2a or 2b or ribavirin) along with pharmaceutical compositions thereof. 
     In addition, the present invention comprises compositions and methods for treating HCV infection in hosts that are co-infected with HIV. Accordingly, the present invention comprises compositions (e.g., kits) comprising an E1-E2 peptide of the invention (e.g., any of SEQ ID NO: 3-139) in association with one or more HIV protease inhibitors, various nucleoside analogs, nonnucleoside reverse transcriptase inhibitors, antivirals, immunomodulators, antiinfectives, tat antagonists, and glycosidase inhibitors. Numerous examples of such anti-HIV agents are set forth in U.S. Pat. Nos. 6,100,277 and 6,245,806, both incorporated herein by reference, and include, but are not limited to, Ro 31-859, KNI-272, AZT, DDI, DDC, 3TC, D4T, PMEA, Ro 5-3335, Ro 24-7429, indinavir, ritonavir, saquinavir, nelfinavir, amprenavir, abacavir, castanospremine, castanospermine 6-butryl ester, N-butyl-1-deoxy-nojirimycin, N-butyl-1-deoxynojirimycin per-butryl ester, 097, acemannan, acyclovir, AD-439, AD-519, adefovir clipivoxil, AL-721, alpha interferon, ansamycin, beta-fluoro-ddA, BMS-232623, BMS-234475, CI-1012, cidofovir, delaviridine, EL-10, efaviren, famciclovir, FTC, hypericin, Compound Q, ISIS 2922, lobucavir, nevirapine, novapren, peptide T, octapeptide, PNU-140690, probacol, stavudine, valaciclovir, virazole, zalcitabine, ABT-378, bropirimine, gamma interferon, interleukin-2, TNF, etanercept, infliximab, fluconalzole, piritrexim, trimetrexate, daunorubicin, leukotriene B4 receptor antagonist, and analogs and prodrugs thereof. Methods for treating HCV in a patient co-infected with HIV comprising administering an E1-E2 peptide of the invention (e.g., any of SEQ ID NOs: 3-139) in association with an anti-HIV agent (e.g., as discussed herein) are also part of the present invention. 
     Kits 
     Kits of the present invention include an E1-E2 peptide of the present invention (e.g., any of SEQ ID NOs: 3-139), preferably combined with a pharmaceutically acceptable carrier, in a pharmaceutical formulation, more preferably in a pharmaceutical dosage form such as a pill, a powder, an injectable liquid, a tablet, dispersible granules, a capsule, a cachet or a suppository. See for example, Gilman et al. (eds.) (1990),  The Pharmacological Bases of Therapeutics,  8th Ed., Pergamon Press; and  Remington&#39;s Pharmaceutical Sciences , supra, Easton, Pa.; Avis et al. (eds.) (1993)  Pharmaceutical Dosage Forms: Parenteral Medications  Dekker, New York; Lieberman et al. (eds.) (1990)  Pharmaceutical Dosage Forms: Tablets  Dekker, New York; and Lieberman et al. (eds.) (1990),  Pharmaceutical Dosage Forms: Disperse Systems  Dekker, New York. In an embodiment of the invention, a kit of the invention also includes one or more other anti-viral agents, for example, any of the substances discussed above (e.g., ribavirin, pegylated interferon alfa-2a, pegylated interferon alfa-2b or an anti-HIV agent). 
     A kit of the invention can also include a package insert. The package insert may include information concerning the pharmaceutical compositions and dosage forms in the kit. Generally, such information aids patients and physicians in using the enclosed pharmaceutical compositions and dosage forms effectively and safely. For example, the following information regarding an E1-E2 peptide of the invention or other anti-viral agent, included in the kit, may be supplied in the insert: pharmacokinetics, pharmacodynamics, clinical studies, efficacy parameters, indications and usage, contraindications, warnings, precautions, adverse reactions, overdosage, proper dosage and administration, how supplied, proper storage conditions, references and patent information. 
     The E1-E2 peptide of the invention (e.g., SEQ ID NOs: 3-139) and the other anti-viral agent can be supplied, in the kit, as separate compositions or combined into a single composition. For example, the compositions can be supplied within a single, common pharmaceutical dosage form (e.g., pill or tablet) as in separate pharmaceutical dosage forms (e.g., two separate pills or tablets). 
     Dosage and Administration 
     Pharmaceutical composition of the invention may be administered, for example, by any parenteral (e.g., subcutaneous injection, intramuscular injection, intravenous injection) or non-parenteral route (e.g., orally, nasally). 
     Pills and capsules of the invention can be administered orally. Injectable compositions can be administered with medical devices known in the art; for example, by injection with a hypodermic needle including the REDIPEN® or the NOVOLET® Novo Pen discussed above. 
     Injectable pharmaceutical compositions of the invention can also be administered with a needleless hypodermic injection device; such as the devices disclosed in U.S. Pat. No. 5,399,163; 5,383,851; 5,312,335; 5,064,413; 4,941,880; 4,790,824 or 4,596,556. 
     Peptides of the invention can be administered, for example, three times a day, twice a day, once a day, three times weekly, twice weekly or once weekly. 
     The daily dose of an anti-viral agent administered in association with a peptide of the present invention (e.g., any of SEQ ID NOs: 3-139) is, where possible, administered accordance with the  Physicians&#39; Desk Reference  2003 ( Physicians&#39; Desk Reference,  57th Ed); Medical Economics Company; ISBN: 1563634457; 57th edition (November 2002). The proper dosage can, however, be altered by a clinician to compensate for particular characteristics of the subject receiving the therapy depending, for example, on the potency of the compound administered, side-effects, age, weight, medical condition, overall health and response. 
     The term “therapeutically effective amount” means that amount of a therapeutic agent or substance (e.g., peptide of the present invention (e.g., any of SEQ ID NOs: 3-139), interferon or ribavirin) that will elicit a biological or medical response of a tissue, system, subject or host that is being sought by the administrator (such as a researcher, doctor or veterinarian) which includes alleviation of the symptoms of Flaviviridae virus (e.g., HCV) infection and the prevention, slowing or halting of progression of Flaviviridae virus (e.g., HCV) infection and its symptom(s) to any degree including prevention of the infection of a host with a Flaviviridae virus (e.g., HCV) following transplant of a liver into said host. For example, in one embodiment, a “therapeutically effective dosage” of an E1-E2 peptide of the present invention (e.g., SEQ ID NOs: 3-139) or a combination including another anti-viral agent (e.g., ribavirin and/or pegylated or unpegylated interferon alfa-2a or 2b) results in the eradication of detectable Flaviviridae Viral RNA (e.g., HCV RNA) for any period of time, for example, 12 or more weeks (e.g., 24 weeks). Detection of viral RNA in a host can be done easily using conventional, well-known methods in the art. See also the Physicians&#39; Desk Reference (“PDR”) for the therapeutically effective dose and dosage regimens approved by the U.S. Food and Drug Administration. 
     A person suffering from chronic hepatitis C infection may exhibit one or more of the following signs or symptoms: 
     (a) elevated ALT,
 
(b) positive test for anti-HCV antibodies,
 
(c) presence of HCV as demonstrated by a positive test for HCV-RNA,
 
(d) clinical stigmata of chronic liver disease,
 
(e) hepatocelluar damage.
 
     Ideally, though not necessarily, an infected host who is administered a composition of the invention will, eventually, exhibit no detectable HCV RNA is his body for a period of time (e.g., 12 or more weeks). 
     The term “no detectable HCV-RNA” in the context of the present invention means that there is less than about 100 copies of HCV-RNA per ml of serum of the patient as measured by quantitative, multi-cycle reverse transcriptase PCR (rtPCT) methodology. Such PCR based assays are conventional and very well known in the art. In general, rtPCR is performed by isolating the RNA from a specimen, reverse-transcribing it to generate cDNAs, amplifying specific nucleic acid sequences by PCR, and then using a variety of methods to detect the amplified sequences (Urdea et al., Clin. Chem. 43:1507-1511 (1997)). Preferably, a patient with no detectable HCV-RNA comprises 0 copies per ml of serum. 
     In one embodiment, a host administered a composition of the present invention exhibits a sustained virologic response. The term “sustained virologic response” as used in the context of the present invention means that there is no detectable HCV-RNA in the serum of patients treated in accordance with the present invention for at least 24 weeks after the end of the combined therapy treatment. Preferably, the period of sustained virologic response is at least one year—or longer—after the end of treatment. 
     A “therapeutically effective” dosage or amount of an E1-E2 peptide of the present invention (e.g., SEQ ID NOs: 3-139; e.g., for treating or preventing Flaviviridae virus (e.g., HCV) infection) is about 100 μg three times per day or about 300 μg once a day. However, as discussed above, this dosage may be adjusted up or down by a clinician depending on the circumstances of each particular case. 
     As discussed herein, methods of the present invention include administering an E1-E2 peptide of the present invention (e.g., any of SEQ ID NOs: 3-139) along with pegylated or unpegylated interferon alfa-2a, pegylated or unpegylated interferon alfa-2b, pegylated or unpegylated interferon alfa-2c, pegylated or unpegylated interferon alfa n-1, pegylated or unpegylated interferon alfa n-3, unpegylated pegylated consensus interferon, ribavirin or any combination thereof. 
     A therapeutically effective dosage of interferon alfa-2b (e.g., INTRON-A®), particularly for the treatment of chronic hepatitis C is 3 million IU (international units) three times a week (TIW) administered subcutaneously or intramuscularly. In patients tolerating therapy with normalization of serum alanine aminotransferase (ALT) at 16 weeks of treatment, INTRON A® therapy should be extended to 18 to 24 months (72 to 96 weeks) at 3 million IU TIW to improve the sustained response rate. 
     If severe adverse reactions develop during INTRON A® treatment, the dose should be modified (50% reduction) or therapy should be discontinued as indicated below. If intolerance persists after dose adjustment, INTRON A® therapy should be discontinued. 
     The recommended dose of PEG-interferon alfa-2b (e.g., PEG-INTRON®) regimen is from about 0.5 to about 1.5 μg/kg/week, preferably 1.0 μg/kg/week for one year. 
     A therapeutically effective dosage of interferon alfa-2a (e.g., ROFERON-A®), particularly for the treatment of chronic hepatitis C, is 3 MIU three times a week (TIW) administered subcutaneously or intramuscularly for 12 months (48 to 52 weeks). As an alternative, patients may be treated with an induction dose of 6 MIU TIW for the first 3 months (12 weeks) followed by 3 MIU TIW for 9 months (36 weeks). 
     Patients who tolerate and partially or completely respond to therapy with ROFERON-A® but relapse following its discontinuation may be re-treated. Re-treatment with either 3 MIU TIW or with 6 MIU TIW for 6 to 12 months may be considered. 
     A temporary dose reduction by 50% is recommended in patients who do not tolerate the prescribed dose of ROFERON-A®. If adverse events resolve, treatment with the original prescribed dose can be re-initiated. In patients who cannot tolerate the reduced dose, cessation of therapy, at least temporarily, is recommended. 
     The recommended dose of PEG-interferon alfa-2a (e.g., PEGASYS®) monotherapy is 180 μg (1.0 mL) once weekly for 48 weeks by subcutaneous (SC) administration in the abdomen or thigh. 
     A therapeutically effective dosage of consensus interferon alfa (e.g., INFERGEN®), particularly for treatment of chronic HCV infection, is 9 mcg TIW administered SC as a single injection for 24 weeks. At least 48 hours should elapse between doses of INFERGEN®. 
     Patients who tolerated previous interferon therapy and did not respond or relapsed following its discontinuation may be subsequently treated with 15 mcg of INFERGEN® TIW administered SC as a single injection for up to 48 weeks. 
     For patients who experience a severe adverse reaction on INFERGEN®, dosage should be withheld temporarily. If the adverse reaction does not become tolerable, therapy should be discontinued. Dose reduction to 7.5 mcg may be necessary following an intolerable adverse event. 
     If adverse reactions continue to occur at the reduced dosage, the physician may discontinue treatment or reduce dosage further. However, decreased efficacy may result from continued treatment at dosages below 7.5 mcg. 
     During subsequent treatment for 48 weeks with 15 mcg of INFERGEN®, up to 36% of patients required dose reductions in 3 mcg increments. 
     A therapeutically effective does of albumin-interferon-alpha (e.g., ALBUFERON®) is about 120 mcg or about 180 mcg or about 240 mcg or about 320 mcg or about 400 mcg or about 500 mcg per day subcutaneously. 
     A therapeutically effective dose of ribavirin (e.g., REBETROL®) depends on the patient&#39;s body weight. The recommended dose of REBETOL® is provided, below, in Table 1. 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 Recommended Dosing 
               
            
           
           
               
               
            
               
                 Body weight 
                 REBETOL Capsules 
               
               
                   
               
            
           
           
               
               
               
            
               
                 &lt;/=75 
                 kg 
                 2 × 200-mg capsules AM, 
               
               
                   
                   
                 3 × 200-mg capsules PM daily p.o. 
               
               
                 &gt;75 
                 kg 
                 3 × 200 mg capsules AM, 
               
               
                   
                   
                 3 × 200 mg capsules PM daily p.o. 
               
               
                   
               
            
           
         
       
     
     The recommended duration of treatment with ribavirin (e.g., REBETOL®) for patients previously untreated with interferon is 24 to 48 weeks. The duration of treatment should be individualized to the patient depending on baseline disease characteristics, response to therapy, and tolerability of the regimen. After 24 weeks of treatment, virologic response should be assessed. Treatment discontinuation should be considered in any patient who has not achieved an HCV RNA below the limit of detection of the assay by 24 weeks. 
     In patients who relapse following interferon therapy, the recommended duration of treatment with ribavirin (e.g., REBETOL®) is 24 weeks. 
     REBETOL® may be administered without regard to food, but should be administered in a consistent manner with respect to food intake. 
     A combination of interferon alfa-2b and ribavirin (e.g., REBETRON®) can also be administered in association with an E1-E2 peptide of the present invention (e.g., SEQ ID NOs: 3-139). 
     The recommended duration of REBETRON® treatment for patients previously untreated with interferon is 24 to 48 weeks. The duration of treatment should be individualized to the patient depending on baseline disease characteristics, response to therapy, and tolerability of the regimen. After 24 weeks of treatment, virologic response should be assessed. Treatment discontinuation should be considered in any patient who has not achieved an HCV RNA below the limit of detection of the assay by 24 weeks. In patients who relapse following interferon therapy, the recommended duration of treatment is 24 weeks. 
     The recommended dosage of a combination of ribavirin (e.g., REBETROL®) and interferon alfa-2b (e.g., INTRON-A®) depends on patient body weigh. The adult dosage regimen is set forth below in Table 2: 
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 Recommended Adult Dosing 
               
            
           
           
               
               
               
            
               
                 Body weight 
                 REBETOL Capsules 
                 INTRON A Injection 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 &lt;/=75 
                 kg 
                 2 × 200-mg capsules AM, 
                 3 million IU 3 times 
               
               
                   
                   
                 3 × 200-mg capsules PM 
                 weekly s.c. 
               
               
                   
                   
                 daily p.o. 
               
               
                 &gt;75 
                 kg 
                 3 × 200-mg capsules AM, 
                 3 million IU 3 times 
               
               
                   
                   
                 3 × 200-mg capsules PM 
                 weekly s.c. 
               
               
                   
                   
                 daily p.o. 
               
               
                   
               
            
           
         
       
     
     The pediatric dosage regimen, for the combination, is set forth below in Table 3: 
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 Pediatric Dosing 
               
            
           
           
               
               
               
            
               
                 Body weight 
                 REBETOL Capsules 
                 INTRON A Injection 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 25-36 
                 kg 
                 1 × 200-mg capsule AM 
                 3 million IU/m 2  3 times 
               
               
                   
                   
                 1 × 200-mg capsule PM 
                 weekly s.c. 
               
               
                   
                   
                 daily p.o. 
               
               
                 37-49 
                 kg 
                 1 × 200-mg capsule AM 
                 3 million IU/m 2  3 times 
               
               
                   
                   
                 2 × 200-mg capsules PM 
                 weekly s.c. 
               
               
                   
                   
                 daily p.o. 
               
               
                 50-61 
                 kg 
                 2 × 200-mg capsules AM 
                 3 million IU/m 2  3 times 
               
               
                   
                   
                 2 × 200-mg capsules PM 
                 weekly s.c. 
               
               
                   
                   
                 daily p.o. 
               
               
                 &gt;61 
                 kg 
                 Refer to adult dosing table 
                 Refer to adult dosing table 
               
               
                   
               
            
           
         
       
     
     Dosage modification of REBETOL®/INTRON-A® treatment is indicated when adverse reactions are observed in the patient. For example, in patients with a history of stable cardiovascular disease, a permanent dose reduction is required if the patient&#39;s hemoglobin decreases by &gt;1=2g/dL during any 4-week period. In addition, for these cardiac history patients, if the patient&#39;s hemoglobin remains &lt;12g/dL after 4 weeks on a reduced dose, the patient should discontinue combination REBETOL®/INTRON-A® therapy. 
     It is recommended that a patient whose hemoglobin level falls below 10 g/dL have his/her REBETOL® dose reduced to 600 mg daily (1×200-mg capsule AM, 2×200-mg capsules PM). A patient whose hemoglobin level falls below 8.5 g/dL should be permanently discontinued from REBETOL®/INTRON A® therapy. 
     When administered in combination with REBETOL®, the recommended dose of PEG-Intron® is 1.5 micrograms/kg/week. The recommended dose of REBETOL® is 800 mg/day in 2 divided doses: two capsules (400 mg) with breakfast and two capsules (400 mg) with dinner. REBETOL® should not be used in patients with creatinine clearance &lt;50 mL/min. 
     EXAMPLES 
     The following examples are intended to exemplify and further clarify what is the present invention and should not be construed to limit the present invention. The present invention should not be limited by any mechanism or theory presented herein. Any composition disclosed in any of the following examples along with any disclosed method is part of the present invention. 
     Example 1 
     Identification and Characterization of Inhibitory E1-E2 Peptides 
     Expression of HCV envelope protein. The envelope region of HCV was PCR amplified from FKI389/core3′ plasmid (Pietschmann et al., J. Virol. 76(8):4008-21 (2002)) with the primers GATCAAGCTTATGGGTTGCTCCTTTTCTATCTTC (SEQ ID NO: 140) and GATCAGATCTAGTGATAATCCGGAGTCGAACTCGATAGTC (SEQ ID NO: 141). The amplified product was digested with HindIII and XbaI and ligated into the pCMV-hygro (Invitrogen Corp.; Carlsbad, Calif.). The expression of the envelope proteins was confirmed with Western blot. 
     HCV pseudotype particle generation. Single cycle HCV pseudoparticles are composed of a replication-defective HIV genome and HCV envelope proteins. These pseudoparticles were made by transfecting 293T cells with 5 ug of each pNL43E-R-luc (Chen et al., J. Virol. 68(2):654-60 (1994)) and plasmid expressing HCV envelope proteins pCMV/E1-2 with profection transfection kit from Promega (Madison, Wis.). The medium was refreshed 12-24 hours after transfection and supernatant was collected 48 hours after transfection. The supernatant from a transfection of only pNL43E-R-luc was used each time as a control for non specific entry events. 
     Peptide library preparation. The peptide library was synthetically assembled on MBHA Rink amide or NovaSyn TG Sieber resin (at 5 umol per peptide) in 96-well microtiter plate by a MultiPep synthesizer (Intavis AG, Germany) with standard Fmoc chemistry. After successful completion of the synthesis, the resins were washed with dichloromethane five times and completely dried under vacuum in the MultiPep. The microtiter plate was removed from the MultiPep and placed on top of a 96-well collection plate (2 ml volume per well). 200 ul of concentrated (80-90%) TFA with proper scavengers such as water and triisopropylsilane were added to the microtiter wells containing the assembled peptide resin. This cleavage process was repeated three additional times with 10 min intervals. The collected cleavage solution was let to stand at room temperature for 2 hours of deprotection. Each peptide was then transferred to a 15-ml polypropylene tube containing 10 ml anhydrous ethyl ether. The tubes were spun down in a clinical centrifuge. The ether phase was carefully decanted. The precipitated peptides were taken up in water and lyophilized over night. LCMS analysis was conducted for each peptide to verify the molecular weight and assess purity. The peptides were finally dissolved in 100% DMSO and used in assays without further purification unless otherwise noted for selected bioactive peptides. Occasionally, the bioactive peptides were synthesized at larger scale (250 umol) by an ABI model 431A peptide synthesizer (Applied Biosystems, Foster City, Calif.) using the same chemistry as mentioned above. 
     Infection of hepatoma cell lines with HCV pseudotype particles and screen for inhibitory peptides. The hepatoma cells, Huh7, was seeded at 8000 cells in 90 ul medium in 96-well plate. In the case of the inhibitor screen, the inhibitor was incubated with cells for one hour at 37° C. and then 50 ul viral supernatant was added to the cells 24 hours after seeding. The viral stock was pre-tittered and diluted to yield approximately 10,000 to 20,000 RLU. The cells were incubated at 37° C. with 5% CO 2  for additional 72 hours and were harvested for luciferase assay. Peptide stocks were prepared in 100% DMSO at 10 mg/ml and were first screened at 100 ug/ml and then a dose responsive curve was generated with 10 points 3-fold titration starting from 100 ug/ml. 
     The specificity of the peptides were counter-screened with AMLV and HIV pseudotyped viruses using the same infection protocol. The results of the entry assay, corresponding to the peptides tested, are shown below in Table 4. 
     Results. 
     
       
         
           
               
             
               
                 TABLE 4 
               
             
            
               
                   
               
               
                 Screen of the peptide library. 
               
            
           
           
               
               
               
            
               
                   
                   
                 AMLVpp 
               
               
                 Peptides 
                 HCVpp % inh 
                 % inh 
               
               
                   
               
            
           
           
               
               
               
            
               
                 Y-E-V-R-N-V-S-G-V-Y-H-V-T-N-D-C 
                 35 
                 18 
               
               
                 (SEQ ID NO: 3) 
               
               
                   
               
               
                 G-V-Y-H-V-T-N-D-C-S-N-A-S-I-V-Y 
                 −23 
                 −6 
               
               
                 (SEQ ID NO: 4) 
               
               
                   
               
               
                 D-C-S-N-A-S-I-V-Y-E-A-A-D-M-I-M 
                 −4 
                 −2 
               
               
                 (SEQ ID NO: 5) 
               
               
                   
               
               
                 V-Y-E-A-A-D-M-I-M-H-T-P-G-C-V-P 
                 −13 
                 10 
               
               
                 (SEQ ID NO: 6) 
               
               
                   
               
               
                 I-M-H-T-P-G-C-V-P-C-V-R-E-N-N-S 
                 3 
                 −4 
               
               
                 (SEQ ID NO: 7) 
               
               
                   
               
               
                 V-P-C-V-R-E-N-N-S-S-R-C-W-V-A-L 
                 −22 
                 14 
               
               
                 (SEQ ID NO: 8) 
               
               
                   
               
               
                 N-S-S-R-C-W-V-A-L-T-P-T-L-A-A-R 
                 5 
                 28 
               
               
                 (SEQ ID NO: 9) 
               
               
                   
               
               
                 A-L-T-P-T-L-A-A-R-N-A-S-V-P-T-T 
                 53 
                 1 
               
               
                 (SEQ ID NO: 10) 
               
               
                   
               
               
                 A-R-N-A-S-V-P-T-T-T-I-R-R-H-V-D 
                 −26 
                 24 
               
               
                 (SEQ ID NO: 11) 
               
               
                   
               
               
                 T-T-T-I-R-R-H-V-D-L-L-V-G-A-A-A 
                 31 
                 −5 
               
               
                 (SEQ ID NO: 12) 
               
               
                   
               
               
                 V-D-L-L-V-G-A-A-A-L-C-S-A-M-Y-V 
                 39 
                 −13 
               
               
                 (SEQ ID NO: 13) 
               
               
                   
               
               
                 A-A-L-C-S-A-M-Y-V-G-D-L-C-G-S-V 
                 39 
                 −42 
               
               
                 (SEQ ID NO: 14) 
               
               
                   
               
               
                 Y-V-G-D-L-C-G-S-V-F-L-V-A-Q-L-F 
                 16 
                 −31 
               
               
                 (SEQ ID NO: 15) 
               
               
                   
               
               
                 S-V-F-L-V-A-Q-L-F-T-F-S-P-R-R-H 
                 3 
                 −148 
               
               
                 (SEQ ID NO: 16) 
               
               
                   
               
               
                 L-F-T-F-S-P-R-R-H-E-T-V-Q-D-C-N 
                 9 
                 16 
               
               
                 (SEQ ID NO: 17) 
               
               
                   
               
               
                 R-H-E-T-V-Q-D-C-N-C-S-I-Y-P-G-H 
                 5 
                 17 
               
               
                 (SEQ ID NO: 18) 
               
               
                   
               
               
                 C-N-C-S-I-Y-P-G-H-V-T-G-H-R-M-A 
                 49 
                 26 
               
               
                 (SEQ ID NO: 19) 
               
               
                   
               
               
                 G-H-V-T-G-H-R-M-A-W-D-M-M-M-N-W 
                 43 
                 6 
               
               
                 (SEQ ID NO: 20) 
               
               
                   
               
               
                 M-A-W-D-M-M-M-N-W-S-P-T-A-A-L-V 
                 32 
                 3 
               
               
                 (SEQ ID NO: 21) 
               
               
                   
               
               
                 N-W-S-P-T-A-A-L-V-V-S-Q-L-L-R-I 
                 54 
                 −11 
               
               
                 (SEQ ID NO: 22) 
               
               
                   
               
               
                 L-V-V-S-Q-L-L-R-I-P-Q-A-V-V-D-M 
                 3 
                 −1 
               
               
                 (SEQ ID NO: 23) 
               
               
                   
               
               
                 R-I-P-Q-A-V-V-D-M-V-A-G-A-H-W-G 
                 25 
                 −2 
               
               
                 (SEQ ID NO: 24) 
               
               
                   
               
               
                 D-M-V-A-G-A-H-W-G-V-L-A-G-L-A-Y 
                 27 
                 14 
               
               
                 (SEQ ID NO: 25) 
               
               
                   
               
               
                 W-G-V-L-A-G-L-A-Y-Y-S-M-V-G-N-W 
                 50 
                 27 
               
               
                 (SEQ ID NO: 26) 
               
               
                   
               
               
                 A-Y-Y-S-W-V-G-N-W-A-K-V-L-I-V-M 
                 39 
                 −2 
               
               
                 (SEQ ID NO: 27) 
               
               
                   
               
               
                 N-W-A-K-V-L-I-V-M-L-L-F-A-G-V-D 
                 13 
                 −1 
               
               
                 (SEQ ID NO: 28) 
               
               
                   
               
               
                 V-M-L-L-F-A-G-V-D-G-G-T-Y-V-T-G 
                 −22 
                 11 
               
               
                 (SEQ ID NO: 29) 
               
               
                   
               
               
                 V-D-G-G-T-Y-V-T-G-G-T-M-A-K-N-T 
                 2 
                 −9 
               
               
                 (SEQ ID NO: 30) 
               
               
                   
               
               
                 T-G-G-T-N-A-K-N-T-L-G-I-T-S-L-F 
                 41 
                 −2 
               
               
                 (SEQ ID NO: 31) 
               
               
                   
               
               
                 N-T-L-G-I-T-S-L-F-S-P-G-S-S-Q-K 
                 11 
                 2 
               
               
                 (SEQ ID NO: 32) 
               
               
                   
               
               
                 L-F-S-P-G-S-S-Q-K-I-Q-L-V-N-T-N 
                 61 
                 −49 
               
               
                 (SEQ ID NO: 33) 
               
               
                   
               
               
                 Q-K-I-Q-L-V-N-T-N-G-S-W-H-I-N-R 
                 6 
                 13 
               
               
                 (SEQ ID NO: 34) 
               
               
                   
               
               
                 T-N-G-S-W-H-I-N-R-T-A-L-N-C-N-D 
                 29 
                 30 
               
               
                 (SEQ ID NO: 35) 
               
               
                   
               
               
                 N-R-T-A-L-N-C-N-D-S-L-N-T-G-F-L 
                 23 
                 18 
               
               
                 (SEQ ID NO: 36) 
               
               
                   
               
               
                 N-D-S-L-N-T-G-F-L-A-A-L-F-Y-V-H 
                 14 
                 15 
               
               
                 (SEQ ID NO: 37) 
               
               
                   
               
               
                 F-L-A-A-L-F-Y-V-H-K-F-N-S-S-G-C 
                 23 
                 −44 
               
               
                 (SEQ ID NO: 38) 
               
               
                   
               
               
                 V-H-K-F-N-S-S-G-C-P-E-R-M-A-S-C 
                 −11 
                 −15 
               
               
                 (SEQ ID NO: 39) 
               
               
                   
               
               
                 G-C-P-E-R-M-A-S-C-S-P-I-D-A-F-A 
                 35 
                 −4 
               
               
                 (SEQ ID NO: 40) 
               
               
                   
               
               
                 S-C-S-P-I-D-A-F-A-Q-G-W-G-P-I-T 
                 −11 
                 25 
               
               
                 (SEQ ID NO: 4l) 
               
               
                   
               
               
                 F-A-Q-G-W-G-P-I-T-Y-N-E-S-H-S-S 
                 49 
                 15 
               
               
                 (SEQ ID NO: 42) 
               
               
                   
               
               
                 I-T-Y-N-E-S-H-S-S-D-Q-R-P-Y-C-W 
                 −13 
                 17 
               
               
                 (SEQ ID NO: 43) 
               
               
                   
               
               
                 S-S-D-Q-R-P-Y-C-W-H-Y-A-P-R-P-C 
                 14 
                 15 
               
               
                 (SEQ ID NO: 44) 
               
               
                   
               
               
                 C-W-H-Y-A-P-R-P-C-G-I-V-P-A-A-Q 
                 63 
                 −8 
               
               
                 (SEQ ID NO: 45) 
               
               
                   
               
               
                 P-C-G-I-V-P-A-A-Q-V-C-G-P-V-Y-C 
                 29 
                 −2 
               
               
                 (SEQ ID NO: 46) 
               
               
                   
               
               
                 A-Q-V-C-G-P-V-Y-C-F-T-P-S-P-V-V 
                 40 
                 −8 
               
               
                 (SEQ ID NO: 47) 
               
               
                   
               
               
                 Y-C-F-T-P-S-P-V-V-V-G-T-T-D-R-F 
                 6 
                 21 
               
               
                 (SEQ ID NO: 48) 
               
               
                   
               
               
                 V-V-V-G-T-T-D-R-F-G-V-P-T-Y-S-W 
                 37 
                 −22 
               
               
                 (SEQ ID NO: 49) 
               
               
                   
               
               
                 R-F-G-V-P-T-Y-S-W-G-E-N-E-T-D-V 
                 34 
                 33 
               
               
                 (SEQ ID NO: 50) 
               
               
                   
               
               
                 S-W-G-E-N-E-T-D-V-L-L-L-N-N-T-R 
                 23 
                 34 
               
               
                 (SEQ ID NO: 51) 
               
               
                   
               
               
                 D-V-L-L-L-N-N-T-R-P-P-Q-G-N-W-F 
                 10 
                 16 
               
               
                 (SEQ ID NO: 52) 
               
               
                   
               
               
                 T-R-P-P-Q-G-N-W-F-G-C-T-W-M-N-S 
                 59 
                 −42 
               
               
                 (SEQ ID NO: 53) 
               
               
                   
               
               
                 W-F-G-C-T-W-M-N-S-T-G-F-T-K-T-C 
                 39 
                 −15 
               
               
                 (SEQ ID NO: 54) 
               
               
                   
               
               
                 N-S-T-G-F-T-K-T-C-G-C-P-P-C-N-I 
                 23 
                 3 
               
               
                 (SEQ ID NO: 55) 
               
               
                   
               
               
                 T-C-G-G-P-P-C-N-I-G-G-I-C-N-K-T 
                 53 
                 22 
               
               
                 (SEQ ID NO: 56) 
               
               
                   
               
               
                 N-I-G-G-I-G-N-K-T-L-T-C-P-T-D-C 
                 39 
                 20 
               
               
                 (SEQ ID NO: 57) 
               
               
                   
               
               
                 K-T-L-T-C-P-T-D-C-F-R-K-H-P-E-A 
                 50 
                 13 
               
               
                 (SEQ ID NO: 58) 
               
               
                   
               
               
                 D-C-F-R-K-H-P-E-A-T-Y-T-K-C-G-S 
                 26 
                 −14 
               
               
                 (SEQ ID NO: 59) 
               
               
                   
               
               
                 E-A-T-Y-T-K-C-G-S-G-P-W-L-T-P-R 
                 13 
                 17 
               
               
                 (SEQ ID NO: 60) 
               
               
                   
               
               
                 G-S-G-P-W-L-T-P-R-C-L-V-H-Y-P-Y 
                 −15 
                 −8 
               
               
                 (SEQ ID NO: 61) 
               
               
                   
               
               
                 P-R-C-L-V-H-Y-P-Y-R-L-W-H-Y-P-C 
                 10 
                 −42 
               
               
                 (SEQ ID NO: 62) 
               
               
                   
               
               
                 P-Y-R-L-W-H-Y-P-C-T-V-N-F-T-I-F 
                 44 
                 3 
               
               
                 (SEQ ID NO: 63) 
               
               
                   
               
               
                 P-C-T-V-N-F-T-I-F-K-V-R-M-Y-V-G 
                 −2 
                 −30 
               
               
                 (SEQ ID NO: 64) 
               
               
                   
               
               
                 I-F-K-V-R-M-Y-V-G-G-V-E-H-R-L-E 
                 19 
                 −62 
               
               
                 (SEQ ID NO: 65) 
               
               
                   
               
               
                 V-G-G-V-E-H-R-L-E-A-A-C-N-W-T-R 
                 22 
                 34 
               
               
                 (SEQ ID NO: 66) 
               
               
                   
               
               
                 L-E-A-A-C-N-W-T-R-G-E-R-C-N-L-E 
                 26 
                 37 
               
               
                 (SEQ ID NO: 67) 
               
               
                   
               
               
                 T-R-G-E-R-C-N-L-E-D-R-D-R-S-E-L 
                 13 
                 −7 
               
               
                 (SEQ ID NO: 68) 
               
               
                   
               
               
                 L-E-D-R-D-R-S-E-L-S-P-L-L-L-S-T 
                 −15 
                 1 
               
               
                 (SEQ ID NO: 69) 
               
               
                   
               
               
                 E-L-S-P-L-L-L-S-T-T-E-W-Q-V-L-P 
                 10 
                 44 
               
               
                 (SEQ ID NO: 70) 
               
               
                   
               
               
                 S-T-T-E-W-Q-V-L-P-C-S-F-T-T-L-P 
                 44 
                 18 
               
               
                 (SEQ ID NO: 71) 
               
               
                   
               
               
                 L-P-C-S-F-T-T-L-P-A-L-S-T-G-L-I 
                 −2 
                 20 
               
               
                 (SEQ ID NO: 72) 
               
               
                   
               
               
                 L-P-A-L-S-T-G-L-I-H-L-H-Q-N-V-V 
                 19 
                 0 
               
               
                 (SEQ ID NO: 73) 
               
               
                   
               
               
                 L-I-H-L-H-Q-N-V-V-D-V-Q-Y-L-Y-G 
                 22 
                 5 
               
               
                 (SEQ ID NO: 74) 
               
               
                   
               
               
                 V-V-D-V-Q-Y-L-Y-G-I-G-S-A-V-V-S 
                 39 
                 44 
               
               
                 (SEQ ID NO: 75) 
               
               
                   
               
               
                 Y-G-I-G-S-A-V-V-S-F-A-I-K-W-E-Y 
                 7 
                 24 
               
               
                 (SEQ ID NO: 76) 
               
               
                   
               
               
                 V-S-F-A-I-K-W-E-Y-V-L-L-L-F-L-L 
                 96 
                 3 
               
               
                 (SEQ ID NO: 77) 
               
               
                   
               
               
                 E-Y-V-L-L-L-F-L-L-L-A-D-A-R-V-C 
                 38 
                 34 
               
               
                 (SEQ ID NO: 78) 
               
               
                   
               
               
                 L-L-L-A-D-A-R-V-C-A-C-L-W-M-M-L 
                 77 
                 16 
               
               
                 (SEQ ID NO: 79) 
               
               
                   
               
               
                 V-C-A-C-L-W-M-M-L-L-I-A-Q-A-E-A 
                 16 
                 7 
               
               
                 (SEQ ID NO: 80) 
               
               
                   
               
               
                   1 Percentage of cell entry inhibition of hepatitis C virus observed in the presence of the indicated peptide as compared to the uninhibited control. 
               
               
                   2 Percentage of cell entry inhibition of  amphotropic murine  leukemia virus observed in the presence of the indicated peptide as compared to the uninhibited control. 
               
            
           
         
       
     
     The data points for the dose response curve of peptide VSFAIKWEYVLLLFLL (SEQ ID NO: 77) are shown below in tables 5A (HCVpp) and 5B (HIVpp). The peptide of SEQ ID NO: 77 was first serial diluted by the factor of 3 in 100% DMSO from 100 ug/ml and then transferred to the assay plates at 100-fold dilution. The peptide was first incubated with cells and HCVpp (A) or HIVpp (B), respectively, for 30 minutes at 370 C in this experiment. Then, the medium containing the peptide was removed from the cells and virus with peptide was added to the cells. Cells were incubated for 72 hours and then were harvested for luciferase assay. Two separate trials were performed. 
     
       
         
           
               
             
               
                 TABLE 5A 
               
             
            
               
                   
               
               
                 Dose response curve data points for SEQ ID NO: 77 (HCV). 
               
            
           
           
               
               
               
            
               
                 Peptide conc. 
                 RLU units 
                 RLU units 
               
               
                 (log ug/ml) 
                 (1 st  trial) 
                 (2 nd  trial) 
               
               
                   
               
            
           
           
               
               
               
            
               
                 2 
                 11 
                 10 
               
               
                 1.522879 
                 22 
                 67 
               
               
                 1.045758 
                 306 
                 75 
               
               
                 0.568636 
                 544 
                 500 
               
               
                 0.091515 
                 1044 
                 833 
               
               
                 −0.38561 
                 1279 
                 1283 
               
               
                 −0.86273 
                 1866 
                 1762 
               
               
                 −1.33985 
                 2564 
                 2703 
               
               
                 −1.33985 
                 2998 
                 3512 
               
               
                 −1.33985 
                 2090 
                 3359 
               
               
                   
                 1494 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 5B 
               
             
            
               
                   
               
               
                 Dose response curve data points for SEQ ID NO: 77 (HIV). 
               
            
           
           
               
               
               
            
               
                 Peptide conc. 
                 RLU units 
                 RLU units 
               
               
                 (log ug/ml) 
                 (1 st  trial) 
                 (2 nd  trial) 
               
               
                   
               
            
           
           
               
               
               
            
               
                 2 
                 435408 
                 543239 
               
               
                 1.522879 
                 787025 
                 683636 
               
               
                 1.045758 
                 740592 
                 744482 
               
               
                 0.568636 
                 561454 
                 612198 
               
               
                 0.091515 
                 674698 
                 651004 
               
               
                 −0.38561 
                 732652 
                 734586 
               
               
                 −0.86273 
                 676303 
                 639921 
               
               
                 −1.33985 
                 815312 
                 754404 
               
               
                   
               
            
           
         
       
     
     In addition, the peptide of SEQ ID NO: 77 was mutated at several positions and assayed in the HCV entry assay discussed above. The peptides generated are shown, below, in table 6 along with the results of the HCV entry assay using each peptide. Generally, the peptide of SEQ ID NO: 77 had its N-terminal three amino acids removed (13-mer) and various residues in the 13-mer were replace with alanine (Ala-scan), lysine (Lys-scan), proline (Pro-scan) or glycine (Gly-scan). The data shown in table 6 indicate the percentage of hepatitis C virus cellular entry, at 30 μM peptide concentration, as compared to the uninhibited control. The assays were performed essentially as described above. 
     
       
         
           
               
             
               
                 TABLE 6 
               
             
            
               
                   
               
               
                 Screen of mutant peptides. 
               
            
           
           
               
               
               
            
               
                   
                   
                 % of control 
               
               
                 Sequence 
                 Description 
                 at ~30 uM 
               
               
                   
               
            
           
           
               
               
               
            
               
                 A-I-K-W-E-Y-V-L-L-L-F-L-L 
                 13-mer 
                 17 
               
               
                 (SEQ ID NO: 81) 
               
               
                   
               
               
                 G-I-K-W-E-Y-V-L-L-L-F-L-L 
                 Gly-scan 
                 22 
               
               
                 (SEQ ID NO: 82) 
               
               
                   
               
               
                 A-G-K-W-E-Y-V-L-L-L-F-L-L 
                 Gly-scan 
                 9 
               
               
                 (SEQ ID NO: 83) 
               
               
                   
               
               
                 A-I-K-W-G-Y-V-L-L-L-F-L-L 
                 Gly-scan 
                 19 
               
               
                 (SEQ ID NO: 84) 
               
               
                   
               
               
                 A-I-K-W-E-Y-V-L-L-L-F-L-L 
                 13-mer 
                 20 
               
               
                 (SEQ ID NO: 85) 
               
               
                   
               
               
                 A-I-K-W-E-Y-V-L-L-L-F-L-L 
                 13-mer 
                 13 
               
               
                 (SEQ ID NO: 86) 
               
               
                   
               
               
                 A-A-K-W-E-Y-V-L-L-L-F-L-L 
                 Ala-scan 
                 14 
               
               
                 (SEQ ID NO: 87) 
               
               
                   
               
               
                 A-I-A-W-E-Y-V-L-L-L-F-L-L 
                 Ala-scan 
                 9 
               
               
                 (SEQ ID NO: 88) 
               
               
                   
               
               
                 A-I-K-A-E-Y-V-L-L-L-F-L-L 
                 Ala-scan 
                 8 
               
               
                 (SEQ ID NO: 89) 
               
               
                   
               
               
                 A-I-K-W-A-Y-V-L-L-L-F-L-L 
                 Ala-scan 
                 13 
               
               
                 (SEQ ID NO: 90) 
               
               
                   
               
               
                 A-I-K-W-E-A-V-L-L-L-F-L-L 
                 Ala-scan 
                 16 
               
               
                 (SEQ ID NO: 91) 
               
               
                   
               
               
                 A-I-K-W-E-Y-A-L-L-L-F-L-L 
                 Ala-scan 
                 17 
               
               
                 (SEQ ID NO: 92) 
               
               
                   
               
               
                 A-I-K-W-E-Y-V-A-L-L-F-L-L 
                 Ala-scan 
                 13 
               
               
                 (SEQ ID NO: 93) 
               
               
                   
               
               
                 A-I-K-W-E-Y-V-L-A-L-F-L-L 
                 Ala-scan 
                 17 
               
               
                 (SEQ ID NO: 94) 
               
               
                   
               
               
                 A-I-K-W-E-Y-V-L-L-L-A-L-L 
                 Ala-scan 
                 8 
               
               
                 (SEQ ID NO: 95) 
               
               
                   
               
               
                 A-I-K-W-E-Y-V-L-L-L-F-A-L 
                 Ala-scan 
                 24 
               
               
                 (SEQ ID NO: 96) 
               
               
                   
               
               
                 A-I-K-W-E-Y-V-L-L-L-F-L-A 
                 Ala-scan 
                 24 
               
               
                 (SEQ ID NO: 97) 
               
               
                   
               
               
                 A-I-K-W-E-Y-V-L-L-F-L-L-L 
                 13-mer 
                 10 
               
               
                 (SEQ ID NO: 98) 
               
               
                   
               
               
                 P-I-K-W-E-Y-V-L-L-L-F-L-L 
                 Pro-scan 
                 21 
               
               
                 (SEQ ID NO: 99) 
               
               
                   
               
               
                 A-I-K-W-E-Y-V-L-L-L-F-L-L 
                 13-mer 
                 6 
               
               
                 (SEQ ID NO: 100) 
               
               
                   
               
               
                 K-I-K-W-E-Y-V-L-L-L-F-L-L 
                 Lys-scan 
                 4 
               
               
                 (SEQ ID NO: 101) 
               
               
                   
               
               
                 A-K-K-W-E-Y-V-L-L-L-E-L-L 
                 Lys-scan 
                 5 
               
               
                 (SEQ ID NO: 102) 
               
               
                   
               
               
                 A-I-K-W-K-Y-V-L-L-L-F-L-L 
                 Lys-scan 
                 1 
               
               
                 (SEQ ID NO: 103) 
               
               
                   
               
            
           
         
       
     
     Example 2 
     The Combinational Effects of an Anti-CD81 Antibody and the Peptide of SEQ ID NO: 77 on HCV Pseudoparticle Entry 
     This example demonstrated that the peptide of SEQ ID NO: 77 can enhance the potency of an anti-CD81 antibody and reduce the amount of anti-CD81 antibody that is needed to achieve HCV entry inhibition. The anti-CD81 antibody and the peptide were titrated in duplicates in a 96-well formatted matrix and tested in an HCV pseudoparticle entry assay. The assays were carried out essentially as described above. The data are shown below in the table 7. 
     
       
         
           
               
             
               
                 TABLE 7 
               
               
                   
               
               
                 Results of HCV pseudoparticle entry assay in the presence 
               
               
                 of the peptide of SEQ ID NO: 77 and an anti-CD81 antibody. 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
            
               
                 CD81 
                 peptide 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 antibody 
                 ug/ml 
                 100 
                 100 
                 25 
                 25 
                 6.25 
                 6.25 
                 1.563 
                 1.563 
               
               
                 ug/ml 
                 RLU 
                 RLU 
                 RLU 
                 RLU 
                 RLU 
                 RLU 
                 RLU 
                 RLU 
                 RLU 
               
               
                   
               
               
                 10 
                 RLU 
                 11 
                 54 
                 9 
                 11 
                 59 
                 8 
                 12 
                 8 
               
               
                 1 
                 RLU 
                 15 
                 1322 
                 60 
                 97 
                 62 
                 183 
                 82 
                 69 
               
               
                 0.5 
                 RLU 
                 425 
                 2378 
                 465 
                 547 
                 639 
                 379 
                 886 
                 1421 
               
               
                 0.25 
                 RLU 
                 895 
                 2056 
                 1329 
                 449 
                 1716 
                 1286 
                 1177 
                 1863 
               
               
                 0.125 
                 RLU 
                 2022 
                 2646 
                 1972 
                 1953 
                 3028 
                 3033 
                 5729 
                 3990 
               
               
                 0.063 
                 RLU 
                 2490 
                 1686 
                 2866 
                 3310 
                 4473 
                 4063 
                 6595 
                 4999 
               
               
                 0.031 
                 RLU 
                 3956 
                 2902 
                 2898 
                 4125 
                 5178 
                 5950 
                 7372 
                 6792 
               
               
                 0.016 
                 RLU 
                 3651 
                 3704 
                 6733 
                 3753 
                 5114 
                 3947 
                 10490 
                 8055 
               
               
                 0.008 
                 RLU 
                 3467 
                 3174 
                 7394 
                 5876 
                 8317 
                 7338 
                 7426 
                 7750 
               
               
                 0.004 
                 RLU 
                 5596 
                 2937 
                 6870 
                 4968 
                 7406 
                 7571 
                 13281 
                 7992 
               
               
                 0.002 
                 RLU 
                 3192 
                 3875 
                 6206 
                 5485 
                 7305 
                 7703 
                 10717 
                 9978 
               
               
                 0.002 
                 RLU 
                 2317 
                 4082 
                 5297 
                 5697 
                 5277 
                 8751 
                 11221 
                 9543 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 CD81 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 antibody 
                 0.391 
                 0.391 
                 0.098 
                 0.098 
                 0 
                 0 
                 0 
                 0 
               
               
                 ug/ml 
                 RLU 
                 RLU 
                 RLU 
                 RLU 
                 RLU 
                 RLU 
                 RLU 
                 RLU 
               
               
                   
               
               
                 10 
                 11 
                 9 
                 16 
                 7 
                 106 
                 9 
                 85 
                 45 
               
               
                 1 
                 392 
                 312 
                 298 
                 141 
                 779 
                 303 
                 1005 
                 470 
               
               
                 0.5 
                 505 
                 1120 
                 1402 
                 491 
                 1608 
                 1338 
                 1686 
                 1356 
               
               
                 0.25 
                 3172 
                 1404 
                 2168 
                 2740 
                 6099 
                 4330 
                 9891 
                 5351 
               
               
                 0.125 
                 5847 
                 4578 
                 3503 
                 7501 
                 14512 
                 9507 
                 15468 
                 8386 
               
               
                 0.063 
                 10137 
                 7624 
                 10587 
                 9989 
                 17164 
                 12430 
                 16250 
                 12146 
               
               
                 0.031 
                 9934 
                 8742 
                 15376 
                 12424 
                 16998 
                 13731 
                 19768 
                 16741 
               
               
                 0.016 
                 12692 
                 9424 
                 15036 
                 12663 
                 17381 
                 17712 
                 17123 
                 15484 
               
               
                 0.008 
                 15805 
                 9670 
                 17882 
                 13398 
                 19216 
                 16711 
                 23553 
                 15269 
               
               
                 0.004 
                 14122 
                 13155 
                 18445 
                 6152 
                 18053 
                 19403 
                 18423 
                 16197 
               
               
                 0.002 
                 13906 
                 13219 
                 20304 
                 13319 
                 10409 
                 14130 
                 17576 
                 15204 
               
               
                 0.002 
                 9828 
                 12349 
                 14565 
                 17382 
                 15086 
                 16310 
                 13542 
                 17922 
               
               
                   
               
               
                 RLU = luciferase units (relative light units). 
               
            
           
         
       
     
     Dose response curves of anti-CD81 antibody with various amounts of peptide were plotted vs. RLU, and the results are summarized below. The data indicate that the concentrations for anti-CD81 antibody to achieve 50% and 90% inhibition were decreased in the presence of the increasing amount of the peptide. When the peptide was present at 10-30% of its IC50 concentration, the IC50 for anti-CD81 was reduced by 3 to 6-fold. Similarly, when the peptide was present at 1% to 25% of its IC75 concentration, the IC75 for the anti-CD81 antibody was reduced by 3 to 9 fold. Thus, the peptide enhances the potency of the anti-CD81 antibody. 
     
       
         
           
               
             
               
                 TABLE 8 
               
             
            
               
                   
               
               
                 IC50 and IC90 of the anti-CD81 antibody in the presence 
               
               
                 of increasing concentrations of peptide of SEQ ID NO: 77. 
               
            
           
           
               
               
               
            
               
                 CD81 + pp75 ug/ml 
                 IC50 
                 IC90 
               
               
                   
               
            
           
           
               
               
               
            
               
                 0.000 
                 0.214 
                 0.639 
               
               
                 0.000 
                 0.189 
                 0.482 
               
               
                 0.098 
                 0.090 
                 0.319 
               
               
                 0.391 
                 0.063 
                 0.378 
               
               
                 1.563 
                 0.024 
                 0.371 
               
               
                 6.250 
                   
                 0.253 
               
               
                 25.000 
                   
                 0.139 
               
               
                 100.000 
                   
                 0.266 
               
               
                   
               
            
           
         
       
     
     Example 3 
     Amino Acid Sequence Requirement for Peptide Activity 
     To determine which amino acids are required to inhibit HCVpp entry, sequential deletions were generated at the amino and carboxy terminus of the peptide of SEQ ID NO: 77 (Table 9). Sequential deletion of the first six amino acids from the amino terminus retained 80 to 90% of inhibition activity; however, a series removal of the six amino acids from the carboxy terminus lost approximately 50% activity. The sensitivity to the carboxy terminus deletions indicates the importance of the residues from the transmembrane domain. The peptide, A-I-K-W-E-Y-V-L-L-L-F-L-L (SEQ ID NO: 106 or 81), retained about 90% activity and is three amino acids shorter than the peptide of SEQ ID NO: 77. 
     
       
         
           
               
             
               
                 TABLE 9 
               
             
            
               
                   
               
               
                 Truncated peptides.¢ 
               
            
           
           
               
               
               
            
               
                 Peptides 
                 Comments 
                 HCVpp % inh 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 V-S-F-A-I-K-W-E-Y-V-L-L-L-F-L-L 
                 wild type 
                   
                 (SEQ ID NO: 77) 
                   
               
               
                   
               
               
                   S-F-A-I-K-W-E-Y-V-L-L-L-F-L-L 
                 N-terminal truncation 
                 91 
                 (SEQ ID NO: 104) 
               
               
                   
               
               
                     F-A-I-K-W-E-Y-V-L-L-L-F-L-L 
                 N-terminal truncation 
                 95 
                 (SEQ ID NO: 105) 
               
               
                   
               
               
                       A-I-K-W-E-Y-V-L-L-L-F-L-L 
                 N-terminal truncation 
                 92 
                 (SEQ ID NO: 106) 
               
               
                   
               
               
                         I-K-W-E-Y-V-L-L-L-F-L-L 
                 N-terminal truncation 
                 88 
                 (SEQ ID NO: 107) 
               
               
                   
               
               
                           K-W-E-Y-V-L-L-L-F-L-L 
                 N-terminal truncation 
                 78 
                 (SEQ ID NO: 108) 
               
               
                   
               
               
                             W-E-Y-V-L-L-L-F-L-L 
                 N-terminal truncation 
                 82 
                 (SEQ ID NO: 109) 
               
               
                   
               
               
                 V-S-F-A-I-K-W-E-Y-V-L-L-L-F-L-L 
                 wild type 
                   
                 (SEQ ID NO: 110) 
               
               
                   
               
               
                 V-S-F-A-I-K-W-E-Y-V-L-L-L-F-L 
                 C-terminal truncation 
                 63 
                 (SEQ ID NO: 111) 
               
               
                   
               
               
                 V-S-F-A-I-K-W-E-Y-V-L-L-L-F 
                 C-terminal truncation 
                 49 
                 (SEQ ID NO: 112) 
               
               
                   
               
               
                 V-S-F-A-I-K-W-E-Y-V-L-L-L 
                 C-terminal truncation 
                 49 
                 (SEQ ID NO: 113) 
               
               
                   
               
               
                 V-S-F-A-I-K-W-E-Y-V-L-L 
                 C-terminal truncation 
                 44 
                 (SEQ ID NO: 114) 
               
               
                   
               
               
                 V-S-F-A-I-K-W-E-Y-V-L 
                 C-terminal truncation 
                 17 
                 (SEQ ID NO: 115) 
               
               
                   
               
               
                 V-S-F-A-I-K-W-E-Y-V 
                 C-terminal truncation 
                 60 
                 (SEQ ID NO: 116) 
               
               
                   
               
               
                 ¢Peptides were dissolved at 5 mM in 100% DMSO and tested at 50 uM in 1% DMSO. 
               
            
           
         
       
     
     Compared to the wild type 13-mer peptide (SEQ ID NO: 106 or 81), the retro peptide of SEQ ID NO: 106 (i.e., LLFLLLVYEWKIA (SEQ ID NO: 107)) and retro-inverso peptide of SEQ ID NO: 106 (i.e., LLFLLLVYEWKIA (SEQ ID NO: 107) with all D-amino acids) peptides completely lost activity, indicating that the overall hydrophobic nature of the retro and retro-inverso peptides is not enough for activity and the sequential order of certain key amino acids plays a leading role. The inverso peptides (SEQ ID NO: 106 with all D-amino acids), however, retained partial but weakened activity. 
     
       
         
           
               
             
               
                 TABLE 10 
               
               
                   
               
               
                 Dose response curve for HCV entry at various concentrations 
               
               
                 of inverso, retro and retro-inverso peptides ¥   
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 nM of 
                   
                   
                   
                   
                   
               
               
                 peptide 
                 inverso 
                 inverso 
                 inverso 
                 retro 
                 retro 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
            
               
                 30000 
                 30 
                 68 
                 12 
                 54 
                 19 
                 34 
                 90 
                 96 
                 80 
                 73 
               
               
                 10000 
                 40 
                 44 
                 41 
                 46 
                 27 
                 52 
                 54 
                 99 
                 55 
                 79 
               
               
                 300 
                 78 
                 62 
                 70 
                 77 
                 46 
                 41 
                 66 
                 79 
                 119 
                 69 
               
               
                 100 
                 67 
                 74 
                 106 
                 84 
                 60 
                 82 
                 101 
                 79 
                 99 
                 72 
               
               
                 30 
                 120 
                 94 
                 91 
                 86 
                 72 
                 45 
                 58 
                 93 
                 92 
                 94 
               
               
                 10 
                 115 
                 97 
                 99 
                 74 
                 86 
                 89 
                 95 
                 93 
                 81 
                 52 
               
               
                 3 
                 109 
                 86 
                 108 
                 74 
                 80 
                 90 
                 99 
                 121 
                 76 
                 62 
               
               
                 1 
                 98 
                 87 
                 73 
                 123 
                 99 
                 88 
                 86 
                 97 
                 81 
                 94 
               
               
                 0.3 
                 118 
                 102 
                 110 
                 112 
                 73 
                 69 
                 98 
                 86 
                 95 
                 88 
               
               
                 0.1 
                 139 
                 111 
                 90 
                 93 
                 117 
                 94 
                 87 
                 114 
                 83 
                 82 
               
               
                 0.1 
                 116 
                 69 
                 91 
                 88 
                 68 
                 101 
                 93 
                 109 
                 96 
                 90 
               
               
                 0.1 
                 122 
                 92 
                 109 
                 112 
                 124 
                 108 
                 98 
                 100 
                 107 
                 107 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 nM of 
                   
                 retro- 
                 retro- 
                 retro- 
                 SEQ ID 
               
               
                 peptide 
                 retro 
                 inverso 
                 inverso 
                 inverso 
                 NO: 81 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
            
               
                 30000 
                 104 
                 110 
                 107 
                 87 
                 103 
                 125 
                 107 
                 95 
                 30 
                 26 
               
               
                 10000 
                 34 
                 63 
                 32 
                 55 
                 80 
                 70 
                 90 
                 73 
                 22 
                 34 
               
               
                 300 
                 54 
                 62 
                 57 
                 71 
                 64 
                 79 
                 94 
                 115 
                 39 
                 31 
               
               
                 100 
                 65 
                 62 
                 99 
                 62 
                 91 
                 102 
                 142 
                 81 
                 69 
                 24 
               
               
                 30 
                 45 
                 64 
                 68 
                 62 
                 76 
                 113 
                 121 
                 110 
                 51 
                 38 
               
               
                 10 
                 68 
                 77 
                 66 
                 100 
                 76 
                 84 
                 128 
                 104 
                 70 
                 71 
               
               
                 3 
                 77 
                 66 
                 88 
                 68 
                 78 
                 92 
                 86 
                 98 
                 82 
                 66 
               
               
                 1 
                 51 
                 88 
                 83 
                 72 
                 91 
                 115 
                 106 
                 115 
                 94 
                 114 
               
               
                 0.3 
                 88 
                 91 
                 91 
                 81 
                 74 
                 99 
                 126 
                 117 
                 90 
                 105 
               
               
                 0.1 
                 72 
                 67 
                 81 
                 100 
                 82 
                 113 
                 98 
                 97 
                 103 
                 79 
               
               
                 0.1 
                 90 
                 102 
                 85 
                 99 
                 92 
                 95 
                 103 
                 88 
                 86 
                 77 
               
               
                 0.1 
                 92 
                 116 
                 106 
                 110 
                 106 
                 107 
                 112 
                 97 
                 104 
                 134 
               
               
                   
               
               
                   ¥ Numbers represent viral entry in the presence of the indicated peptide as a percentage of the uninhibited control. 
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 11 
               
               
                   
               
               
                 Dose response curve for HCV entry at various peptide concentrations. £   
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 uM of 
                 scrambled SEQ 
                 scrambled SEQ 
                 scrambled SEQ 
                   
                   
               
               
                 peptide 
                 ID NO: 138 
                 ID NO: 138 
                 ID NO: 138 
                 SEQ ID NO: 81 
                 SEQ ID NO: 85 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
            
               
                 30 
                 7047 
                 5340 
                 7406 
                 5158 
                 5107 
                 5826 
                 990 
                 667 
                 907 
                 406 
               
               
                 10 
                 9469 
                 9957 
                 12877 
                 7340 
                 8434 
                 6401 
                 2584 
                 3853 
                 2865 
                 3393 
               
               
                 3.333333 
                 7729 
                 11535 
                 12632 
                 8653 
                 8028 
                 10288 
                 1152 
                 2683 
                 2490 
                 2239 
               
               
                 1.111111 
                 6456 
                 7681 
                 9683 
                 9482 
                 9053 
                 7359 
                 2065 
                 2449 
                 2918 
                 4380 
               
               
                 0.3703704 
                 7620 
                 8597 
                 9180 
                 5716 
                 8494 
                 8291 
                 2133 
                 2617 
                 3430 
                 3658 
               
               
                 0.1234568 
                 9257 
                 8961 
                 11382 
                 10746 
                 7229 
                 6598 
                 1665 
                 1759 
                 2304 
                 5077 
               
               
                 0.04115226 
                 12287 
                 13159 
                 13838 
                 13589 
                 10645 
                 10230 
                 3138 
                 5487 
                 6444 
                 7203 
               
               
                 0.01371742 
                 13068 
                 15343 
                 14994 
                 12097 
                 11663 
                 11748 
                 4392 
                 3561 
                 7335 
                 8987 
               
               
                 0.01371742 
                 15761 
                 17272 
                 24285 
                 16582 
                 13218 
                 17842 
                 13679 
                 16041 
                 14360 
                 13526 
               
               
                 0.01371742 
                 20329 
                 16998 
                 20395 
                 15327 
                 17640 
                 13895 
                 12493 
                 16554 
                 13698 
                 15168 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 uM of 
                   
                   
                   
                   
               
               
                   
                 peptide 
                 SEQ ID NO: 86 
                 SEQ ID NO: 98 
                 SEQ ID NO: 100 
                 SEQ ID NO: 103 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
            
               
                   
                 30 
                 1899 
                 1645 
                 1938 
                 2251 
                 1262 
                 1073 
                 2946 
                 4314 
               
               
                   
                 10 
                 2867 
                 1216 
                 2186 
                 2352 
                 1538 
                 1360 
                 2732 
                 4879 
               
               
                   
                 3.333333 
                 2746 
                 2356 
                 2647 
                 2056 
                 4131 
                 3158 
                 3098 
                 4136 
               
               
                   
                 1.111111 
                 3652 
                 3574 
                 3285 
                 2555 
                 3041 
                 2870 
                 3136 
                 4198 
               
               
                   
                 0.3703704 
                 5748 
                 3127 
                 2830 
                 5272 
                 4161 
                 2767 
                 2800 
                 5362 
               
               
                   
                 0.1234568 
                 6445 
                 3869 
                 4583 
                 6873 
                 4241 
                 3590 
                 5848 
                 7916 
               
               
                   
                 0.04115226 
                 8349 
                 8612 
                 6486 
                 6677 
                 7066 
                 7585 
                 10722 
                 14319 
               
               
                   
                 0.01371742 
                 10981 
                 12701 
                 9747 
                 12623 
                 9526 
                 11368 
                 13380 
                 14899 
               
               
                   
                 0.01371742 
                 17159 
                 18427 
                 16027 
                 17299 
                 13637 
                 13231 
                 14290 
                 13421 
               
               
                   
                 0.01371742 
                 19121 
                 16287 
                 19079 
                 17575 
                 14358 
                 15831 
                 19490 
                 13601 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 12 
               
               
                   
               
               
                 Dose response curve for AMLV entry at various peptide concentrations. £   
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 uM of 
                 scrambled SEQ 
                 scrambled SEQ 
                 scrambled SEQ 
                   
                   
               
               
                 peptide 
                 ID NO: 106 
                 ID NO: 106 
                 ID NO: 106 
                 SEQ ID NO: 81 
                 SEQ ID NO: 85 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
            
               
                 30 
                 87785 
                 60410 
                 83010 
                 77083 
                 85612 
                 79287 
                 86600 
                 64937 
                 83257 
                 72040 
               
               
                 10 
                 70668 
                 50409 
                 97446 
                 87834 
                 101416 
                 64206 
                 153900 
                 69448 
                 172763 
                 129890 
               
               
                 3.333333 
                 50674 
                 41738 
                 60859 
                 50020 
                 51236 
                 49388 
                 62658 
                 51388 
                 118949 
                 92146 
               
               
                 1.111111 
                 49084 
                 39443 
                 53349 
                 51341 
                 46069 
                 46019 
                 54439 
                 53032 
                 48628 
                 42996 
               
               
                 0.3703704 
                 48158 
                 45212 
                 49139 
                 49219 
                 51358 
                 50551 
                 48861 
                 55221 
                 43073 
                 44659 
               
               
                 0.1234568 
                 39298 
                 28711 
                 46132 
                 49974 
                 42958 
                 51726 
                 51789 
                 49401 
                 44739 
                 41483 
               
               
                 0.04115226 
                 43854 
                 39721 
                 46556 
                 44480 
                 40734 
                 47413 
                 40104 
                 51496 
                 42604 
                 32390 
               
               
                 0.01371742 
                 49759 
                 43879 
                 46668 
                 38054 
                 46277 
                 49423 
                 46029 
                 39655 
                 43767 
                 55532 
               
               
                 0.01371742 
                 37110 
                 39504 
                 40808 
                 46160 
                 44415 
                 52102 
                 41740 
                 42548 
                 44812 
                 32138 
               
               
                 0.01371742 
                 37232 
                 42195 
                 45601 
                 44163 
                 52921 
                 49326 
                 45150 
                 45203 
                 40068 
                 41172 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 uM of 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 peptide 
                 SEQ ID NO: 86 
                   
                 SEQ ID NO: 98 
                   
                 SEQ ID NO: 100 
                   
                 SEQ ID NO: 103 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 30 
                 76174 
                 71333 
                 81103 
                 70832 
                 76883 
                 56072 
                 116018 
                 90397 
               
               
                 10 
                 70573 
                 72462 
                 111324 
                 59835 
                 135633 
                 74847 
                 182409 
                 156275 
               
               
                 3.3333 
                 53350 
                 39047 
                 59984 
                 48300 
                 70934 
                 59407 
                 60851 
                 69213 
               
               
                 1.1111 
                 40296 
                 43593 
                 45508 
                 44147 
                 45723 
                 43633 
                 49626 
                 41878 
               
               
                 0.3704 
                 43543 
                 47987 
                 42748 
                 48710 
                 42008 
                 39907 
                 49219 
                 41944 
               
               
                 0.1235 
                 37163 
                 47412 
                 45455 
                 45030 
                 46954 
                 44234 
                 53044 
                 67129 
               
               
                 0.0412 
                 42084 
                 47952 
                 41463 
                 41610 
                 39784 
                 45324 
                 45898 
                 42568 
               
               
                 0.0137 
                 42295 
                 44556 
                 44492 
                 44531 
                 45888 
                 43209 
                 44656 
                 41299 
               
               
                 0.0137 
                 43059 
                 48854 
                 47406 
                 49869 
                 52210 
                 102903 
                 45140 
                 43684 
               
               
                 0.0137 
                 37783 
                 49462 
                 51067 
                 61382 
                 41952 
                 46766 
                 39179 
                 81198 
               
               
                   
               
               
                   £ Numbers represent luciferase units observed in the viral entry assays conducted. SEQ ID Nos: 81, 85, 86, 98 and 100 represent the identical wild type 13-mer sequence from independent synthesis. 
               
            
           
         
       
     
     Scrambled 13-mer peptides were clearly different from the wild type 13-mer but yet retained some HCVpp-specific inhibition. The fact that the scrambled 13-mer LKLFEVYLILWLA (SEQ ID NO: 138) still showed some activity, though weakened, implies that what matters for the activity is either the overall hydrophobicity of the peptide and/or the preeminent importance of perhaps as few as two or three of the residues, or the accumulative small contributions from residues in the right places. However, as noted above, since the equally hydrophobic retro and retro-inverso peptides were inactive, and as we shall see below, the contributions to activity are most likely from many residues, thus it is more likely that a significant portion of anti-viral activity comes from residues that happen to be at the approximate right places in the overall scrambled context. The amino acid scanning experiments, below, reaffirmed the notion of collective contributions by many residues. 
     Gly scanning: Glycine substitutions not only eliminated the side chains, but they were expected to introduce much greater local backbone conformational flexibilities. This enhanced conformational freedom can effectively dilute the presence of bioactive conformations, leading to weaker activities. Peptides of SEQ ID NOs: 82-84 and 111 are similarly active or slightly better than wild-type, others were less active. It appears that the N-terminal AIKWEY (SEQ ID NO: 139) sequence can tolerate four (A/I/E/Y) of six substitutions, whereas the Leu-rich carboxy terminal segment is less forgiving to glycine replacement. 
     The data generated in the glycine scanning experiments is set forth below in Table 13. 
     
       
         
           
               
             
               
                 TABLE 13 
               
               
                   
               
               
                 Glycine scanning experiments 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 SEQ ID 
                 SEQ ID 
                 SEQ ID 
                 SEQ ID 
                 SEQ ID 
               
               
                 uM of 
                 NO: 81 
                 NO: 82 
                 NO: 83 
                 NO: 109 
                 NO: 110 
               
               
                 peptide 
                 (% control) 
                 (% control) 
                 (% control) 
                 (% control) 
                 (% control) 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
            
               
                 30 
                 30 
                 26 
                 18 
                 29 
                 18 
                 15 
                 50 
                 28 
                 3 
                 23 
               
               
                 10 
                 22 
                 34 
                 33 
                 29 
                 27 
                 89 
                 66 
                 80 
                 24 
                 18 
               
               
                 0.3 
                 39 
                 31 
                 33 
                 25 
                 17 
                 56 
                 40 
                 69 
                 51 
                 54 
               
               
                 0.1 
                 69 
                 24 
                 33 
                 27 
                 19 
                 47 
                 60 
                 77 
                 61 
                 82 
               
               
                 0.03 
                 51 
                 38 
                 46 
                 41 
                 43 
                 62 
                 61 
                 72 
                 87 
                 71 
               
               
                 0.01 
                 70 
                 71 
                 53 
                 43 
                 76 
                 56 
                 84 
                 111 
                 77 
                 81 
               
               
                 0.003 
                 82 
                 66 
                 71 
                 80 
                 51 
                 66 
                 99 
                 139 
                 102 
                 65 
               
               
                 0.001 
                 94 
                 114 
                 90 
                 66 
                 70 
                 67 
                 93 
                 96 
                 109 
                 91 
               
               
                 0.0003 
                 90 
                 105 
                 68 
                 71 
                 94 
                 83 
                 94 
                 100 
                 107 
                 97 
               
               
                 0.0001 
                 103 
                 79 
                 62 
                 61 
                 75 
                 94 
                 86 
                 103 
                 84 
                 100 
               
               
                 0.00003 
                 86 
                 77 
                 74 
                 88 
                 98 
                 80 
                 88 
                 110 
                 119 
                 104 
               
               
                 0.00003 
                 104 
                 134 
                 118 
                 120 
                 128 
                 94 
                 93 
                 109 
                 87 
                 90 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 SEQ ID 
                 SEQ ID 
                 SEQ ID 
                 SEQ ID 
                 SEQ ID 
               
               
                 uM of 
                 NO: 84 
                 NO: 111 
                 NO: 112 
                 NO: 113 
                 NO: 114 
               
               
                 peptide 
                 (% control) 
                 (% control) 
                 (% control) 
                 (% control) 
                 (% control) 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
            
               
                 30 
                 22 
                 38 
                 10 
                 22 
                 24 
                 37 
                 41 
                 147 
                 118 
                 19 
               
               
                 10 
                 10 
                 40 
                 22 
                 21 
                 34 
                 51 
                 38 
                 36 
                 30 
                 28 
               
               
                 0.3 
                 37 
                 57 
                 36 
                 42 
                 51 
                 61 
                 46 
                 56 
                 51 
                 34 
               
               
                 0.1 
                 41 
                 39 
                 50 
                 46 
                 67 
                 62 
                 78 
                 72 
                 46 
                 64 
               
               
                 0.03 
                 62 
                 52 
                 42 
                 52 
                 64 
                 79 
                 76 
                 78 
                 93 
                 101 
               
               
                 0.01 
                 72 
                 53 
                 49 
                 81 
                 71 
                 69 
                 101 
                 95 
                 82 
                 113 
               
               
                 0.003 
                 70 
                 70 
                 56 
                 79 
                 83 
                 121 
                 94 
                 116 
                 92 
                 102 
               
               
                 0.001 
                 74 
                 73 
                 65 
                 92 
                 100 
                 88 
                 101 
                 94 
                 101 
                 84 
               
               
                 0.0003 
                 91 
                 81 
                 111 
                 59 
                 71 
                 88 
                 87 
                 121 
                 84 
                 92 
               
               
                 0.0001 
                 62 
                 75 
                 81 
                 86 
                 103 
                 112 
                 89 
                 92 
                 93 
                 85 
               
               
                 0.00003 
                 118 
                 84 
                 82 
                 99 
                 112 
                 74 
                 103 
                 115 
                 85 
                 89 
               
               
                 0.00003 
                 87 
                 110 
                 114 
                 106 
                 111 
                 103 
                 80 
                 101 
                 111 
                 115 
               
               
                   
               
            
           
         
       
     
     Ala scanning: Contrary to glycine, devoid of any side chain, alanine still maintains similar backbone conformational rigidity as other L-amino acids. Most alanine mutants are similar to the wild-type, except for the peptide of SEQ ID NO: 115. These data suggested that the expression of viral entry blocking activity is contributed largely collectively by many constituent residues, except somewhat more significantly by the leucine amino terminal to phenylalanine. 
     The data generated in the alanine scanning experiments is set forth below in Table 14. 
     
       
         
           
               
             
               
                 TABLE 14 
               
               
                   
               
               
                 Alanine scanning experiments 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 SEQ ID 
                 SEQ ID 
                 SEQ ID 
                 SEQ ID 
                 SEQ ID 
                 SEQ ID 
                 SEQ ID 
               
               
                 nM of 
                 NO: 85 
                 NO: 86 
                 NO: 87 
                 NO: 88 
                 NO: 89 
                 NO: 90 
                 NO: 91 
               
               
                 peptide 
                 (% control) 
                 (% control) 
                 (% control) 
                 (% control) 
                 (% control) 
                 (% control) 
                 (% control) 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 30000 
                 70 
                 103 
                 15 
                 27 
                 11 
                 6 
                 8 
                 45 
                 4 
                 12 
                 29 
                 4 
                 12 
                 18 
               
               
                 10000 
                 13 
                 18 
                 27 
                 25 
                 15 
                 23 
                 27 
                 32 
                 24 
                 17 
                 40 
                 14 
                 30 
                 15 
               
               
                 300 
                 18 
                 22 
                 25 
                 30 
                 16 
                 13 
                 42 
                 45 
                 24 
                 27 
                 55 
                 55 
                 17 
                 27 
               
               
                 100 
                 45 
                 50 
                 48 
                 33 
                 19 
                 15 
                 37 
                 57 
                 41 
                 38 
                 51 
                 43 
                 35 
                 32 
               
               
                 30 
                 62 
                 57 
                 59 
                 60 
                 42 
                 51 
                 53 
                 66 
                 66 
                 71 
                 69 
                 63 
                 49 
                 48 
               
               
                 10 
                 90 
                 107 
                 69 
                 67 
                 45 
                 57 
                 56 
                 60 
                 63 
                 57 
                 66 
                 46 
                 59 
                 66 
               
               
                 3 
                 71 
                 88 
                 90 
                 118 
                 92 
                 68 
                 81 
                 93 
                 63 
                 76 
                 106 
                 81 
                 86 
                 110 
               
               
                 1 
                 95 
                 83 
                 80 
                 102 
                 110 
                 93 
                 100 
                 69 
                 85 
                 96 
                 66 
                 98 
                 120 
                 102 
               
               
                 0.3 
                 79 
                 96 
                 96 
                 133 
                 84 
                 75 
                 91 
                 101 
                 71 
                 64 
                 73 
                 94 
                 81 
                 84 
               
               
                 0.1 
                 79 
                 81 
                 86 
                 90 
                 90 
                 108 
                 96 
                 85 
                 84 
                 76 
                 105 
                 98 
                 101 
                 73 
               
               
                 0.1 
                 101 
                 74 
                 87 
                 103 
                 113 
                 90 
                 87 
                 108 
                 104 
                 95 
                 82 
                 106 
                 107 
                 89 
               
               
                 0.1 
                 113 
                 112 
                 103 
                 108 
                 93 
                 104 
                 96 
                 109 
                 96 
                 105 
                 116 
                 96 
                 93 
                 111 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 SEQ ID 
                 SEQ ID 
                 SEQ ID 
                 SEQ ID 
                 SEQ ID 
                 SEQ ID 
                 SEQ ID 
               
               
                 nM of 
                 NO: 92 
                 NO: 93 
                 NO: 94 
                 NO: 115 
                 NO: 95 
                 NO: 96 
                 NO: 97 
               
               
                 peptide 
                 (% control) 
                 (% control) 
                 (% control) 
                 (% control) 
                 (% control) 
                 (% control) 
                 (% control) 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 30000 
                 5 
                 15 
                 32 
                 32 
                 14 
                 28 
                 36 
                 0 
                 7 
                 23 
                 31 
                 31 
                 53 
                 50 
               
               
                 10000 
                 12 
                 27 
                 41 
                 32 
                 36 
                 34 
                 11 
                 38 
                 25 
                 15 
                 33 
                 20 
                 19 
                 37 
               
               
                 300 
                 21 
                 30 
                 32 
                 27 
                 42 
                 33 
                 64 
                 40 
                 18 
                 13 
                 36 
                 26 
                 30 
                 47 
               
               
                 100 
                 32 
                 25 
                 47 
                 42 
                 45 
                 41 
                 54 
                 53 
                 35 
                 53 
                 24 
                 41 
                 46 
                 51 
               
               
                 30 
                 42 
                 64 
                 58 
                 51 
                 58 
                 48 
                 88 
                 72 
                 75 
                 35 
                 63 
                 67 
                 55 
                 80 
               
               
                 10 
                 82 
                 59 
                 71 
                 67 
                 79 
                 86 
                 105 
                 78 
                 64 
                 47 
                 58 
                 73 
                 79 
                 69 
               
               
                 3 
                 68 
                 99 
                 78 
                 87 
                 58 
                 89 
                 102 
                 86 
                 85 
                 52 
                 76 
                 85 
                 72 
                 92 
               
               
                 1 
                 90 
                 80 
                 85 
                 87 
                 81 
                 82 
                 66 
                 93 
                 91 
                 72 
                 124 
                 78 
                 76 
                 92 
               
               
                 0.3 
                 85 
                 61 
                 86 
                 105 
                 104 
                 92 
                 82 
                 91 
                 62 
                 70 
                 91 
                 98 
                 72 
                 102 
               
               
                 0.1 
                 73 
                 115 
                 91 
                 83 
                 99 
                 96 
                 83 
                 118 
                 89 
                 82 
                 95 
                 86 
                 80 
                 101 
               
               
                 0.1 
                 82 
                 89 
                 80 
                 104 
                 79 
                 101 
                 108 
                 124 
                 114 
                 76 
                 100 
                 96 
                 105 
                 102 
               
               
                 0.1 
                 99 
                 130 
                 134 
                 81 
                 115 
                 105 
                 81 
                 86 
                 113 
                 97 
                 72 
                 132 
                 95 
                 97 
               
               
                   
               
            
           
         
       
     
     Pro scanning: Unlike the conformationally permissive glycine, proline is far more restrictive due to the side chain to backbone nitrogen ring closure. Introducing praline into the peptide was aimed at creating local contortion of the peptide backbone and probing if a less aggregating and more water soluble but active mutant peptide can emerge. Only the very amino terminal alanine to proline mutant (SEQ ID NO: 99) was similar to the wild-type peptide, others are less active. This suggested that local backbone contortion would ablate activity. 
     The data generated in the proline scanning experiments is set forth below in Table 15. 
     
       
         
           
               
             
               
                 TABLE 15 
               
               
                   
               
               
                 Proline scanning experiments. 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 SEQ ID 
                 SEQ ID 
                 SEQ ID 
                 SEQ ID 
                 SEQ ID 
                 SEQ ID 
                 SEQ ID 
               
               
                 nM of 
                 NO: 98 
                 NO: 99 
                 NO: 116 
                 NO: 117 
                 NO: 118 
                 NO: 119 
                 NO: 120 
               
               
                 peptide 
                 (% control) 
                 (% control) 
                 (% control) 
                 (% control) 
                 (% control) 
                 (% control) 
                 (% control) 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 30000 
                 19 
                 6 
                 2 
                 9 
                 2 
                 5 
                 49 
                 4 
                 24 
                 33 
                 28 
                 17 
                 38 
                 42 
               
               
                 10000 
                 27 
                 24 
                 24 
                 16 
                 15 
                 19 
                 54 
                 31 
                 16 
                 41 
                 21 
                 7 
                 24 
                 24 
               
               
                 300 
                 21 
                 29 
                 21 
                 29 
                 18 
                 34 
                 48 
                 41 
                 38 
                 29 
                 40 
                 47 
                 33 
                 39 
               
               
                 100 
                 31 
                 41 
                 21 
                 34 
                 49 
                 28 
                 38 
                 54 
                 47 
                 53 
                 40 
                 46 
                 39 
                 39 
               
               
                 30 
                 41 
                 35 
                 28 
                 36 
                 29 
                 46 
                 58 
                 71 
                 63 
                 93 
                 39 
                 79 
                 72 
                 40 
               
               
                 10 
                 47 
                 50 
                 45 
                 53 
                 61 
                 58 
                 75 
                 75 
                 116 
                 83 
                 54 
                 48 
                 73 
                 76 
               
               
                 3 
                 86 
                 52 
                 68 
                 56 
                 68 
                 86 
                 89 
                 66 
                 108 
                 84 
                 94 
                 62 
                 66 
                 76 
               
               
                 1 
                 93 
                 94 
                 75 
                 89 
                 81 
                 93 
                 68 
                 87 
                 74 
                 99 
                 72 
                 68 
                 91 
                 75 
               
               
                 0.3 
                 90 
                 68 
                 84 
                 80 
                 86 
                 76 
                 66 
                 117 
                 101 
                 92 
                 78 
                 77 
                 90 
                 75 
               
               
                 0.1 
                 85 
                 77 
                 64 
                 84 
                 89 
                 74 
                 128 
                 93 
                 80 
                 87 
                 93 
                 76 
                 82 
                 78 
               
               
                 0.1 
                 86 
                 109 
                 108 
                 70 
                 98 
                 105 
                 91 
                 97 
                 103 
                 108 
                 87 
                 85 
                 102 
                 80 
               
               
                 0.1 
                 109 
                 95 
                 101 
                 121 
                 120 
                 77 
                 144 
                 68 
                 110 
                 79 
                 102 
                 126 
                 101 
                 117 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 SEQ ID 
                 SEQ ID 
                 SEQ ID 
                 SEQ ID 
                 SEQ ID 
                 SEQ ID 
                 SEQ ID 
               
               
                 nM of 
                 NO: 121 
                 NO: 122 
                 NO: 123 
                 NO: 124 
                 NO: 125 
                 NO: 126 
                 NO: 127 
               
               
                 peptide 
                 (% control) 
                 (% control) 
                 (% control) 
                 (% control) 
                 (% control) 
                 (% control) 
                 (% control) 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 30000 
                 32 
                 41 
                 51 
                 23 
                 31 
                 49 
                 98 
                 67 
                 68 
                 59 
                 55 
                 80 
                 57 
                 29 
               
               
                 10000 
                 50 
                 23 
                 54 
                 43 
                 61 
                 51 
                 85 
                 60 
                 73 
                 54 
                 43 
                 44 
                 29 
                 27 
               
               
                 300 
                 42 
                 30 
                 76 
                 53 
                 41 
                 44 
                 85 
                 68 
                 63 
                 76 
                 72 
                 85 
                 63 
                 72 
               
               
                 100 
                 44 
                 63 
                 75 
                 59 
                 72 
                 61 
                 66 
                 83 
                 60 
                 58 
                 68 
                 81 
                 77 
                 74 
               
               
                 30 
                 70 
                 82 
                 70 
                 113 
                 74 
                 75 
                 48 
                 71 
                 80 
                 102 
                 83 
                 82 
                 78 
                 83 
               
               
                 10 
                 75 
                 66 
                 85 
                 67 
                 78 
                 76 
                 67 
                 102 
                 97 
                 109 
                 86 
                 76 
                 102 
                 74 
               
               
                 3 
                 85 
                 87 
                 106 
                 80 
                 92 
                 78 
                 80 
                 86 
                 85 
                 82 
                 98 
                 89 
                 66 
                 53 
               
               
                 1 
                 76 
                 110 
                 73 
                 100 
                 108 
                 77 
                 89 
                 102 
                 75 
                 99 
                 88 
                 93 
                 71 
                 85 
               
               
                 0.3 
                 68 
                 84 
                 105 
                 83 
                 80 
                 91 
                 74 
                 88 
                 104 
                 104 
                 88 
                 91 
                 84 
                 81 
               
               
                 0.1 
                 77 
                 95 
                 81 
                 70 
                 78 
                 81 
                 87 
                 98 
                 91 
                 99 
                 83 
                 66 
                 90 
                 86 
               
               
                 0.1 
                 91 
                 115 
                 89 
                 86 
                 104 
                 86 
                 89 
                 104 
                 111 
                 92 
                 89 
                 87 
                 90 
                 75 
               
               
                 0.1 
                 104 
                 90 
                 115 
                 111 
                 117 
                 94 
                 109 
                 97 
                 95 
                 101 
                 104 
                 119 
                 122 
                 113 
               
               
                   
               
            
           
         
       
     
     Lys scanning: Lysine was positively charged under the assay condition. Lysine scanning was aimed at reversing the local hydrophobic character and assessing the consequence to potency. Similar to glycine scanning, the amino terminal substitutions were more tolerant; thus peptides of SEQ ID NOs: 101, 102 and 129 were similar or slightly more potent than the wild-type peptide, while others were less potent than the wild-type peptide. 
     The data generated in the lysine scanning experiments is set forth below in Table 16. 
     
       
         
           
               
             
               
                 TABLE 16 
               
               
                   
               
               
                 Lysine scanning experiments 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 SEQ ID 
                 SEQ ID 
                 SEQ ID 
                 SEQ ID 
                 SEQ ID 
                 SEQ ID 
                 SEQ ID 
               
               
                 nM of 
                 NO: 100 
                 NO: 101 
                 NO: 102 
                 NO: 103 
                 NO: 128 
                 NO: 103 
                 NO: 130 
               
               
                 peptide 
                 (% control) 
                 (% control) 
                 (% control) 
                 (% control) 
                 (% control) 
                 (% control) 
                 (% control) 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 30000 
                 6 
                 22 
                 7 
                 1 
                 7 
                 2 
                 2 
                 18 
                 1 
                 9 
                 9 
                 2 
                 26 
                 4 
               
               
                 10000 
                 5 
                 20 
                 2 
                 18 
                 17 
                 7 
                 9 
                 23 
                 4 
                 7 
                 6 
                 17 
                 38 
                 3 
               
               
                 300 
                 32 
                 29 
                 26 
                 29 
                 29 
                 23 
                 30 
                 29 
                 28 
                 22 
                 15 
                 19 
                 33 
                 19 
               
               
                 100 
                 31 
                 19 
                 26 
                 25 
                 16 
                 25 
                 28 
                 27 
                 46 
                 52 
                 15 
                 27 
                 58 
                 24 
               
               
                 30 
                 53 
                 44 
                 37 
                 28 
                 33 
                 41 
                 29 
                 29 
                 55 
                 59 
                 27 
                 35 
                 74 
                 75 
               
               
                 10 
                 62 
                 58 
                 54 
                 57 
                 67 
                 62 
                 84 
                 67 
                 92 
                 63 
                 43 
                 50 
                 90 
                 102 
               
               
                 3 
                 61 
                 83 
                 52 
                 77 
                 70 
                 66 
                 80 
                 81 
                 81 
                 84 
                 91 
                 81 
                 95 
                 81 
               
               
                 1 
                 76 
                 68 
                 65 
                 90 
                 96 
                 83 
                 104 
                 61 
                 72 
                 99 
                 97 
                 85 
                 114 
                 89 
               
               
                 0.3 
                 88 
                 75 
                 96 
                 103 
                 141 
                 107 
                 93 
                 79 
                 88 
                 64 
                 104 
                 83 
                 103 
                 100 
               
               
                 0.1 
                 110 
                 85 
                 83 
                 107 
                 104 
                 102 
                 117 
                 92 
                 86 
                 80 
                 80 
                 93 
                 122 
                 84 
               
               
                 0.1 
                 115 
                 83 
                 77 
                 104 
                 89 
                 108 
                 104 
                 77 
                 102 
                 107 
                 92 
                 87 
                 106 
                 96 
               
               
                 0.1 
                 92 
                 111 
                 119 
                 101 
                 98 
                 106 
                 131 
                 88 
                 103 
                 87 
                 101 
                 120 
                 105 
                 93 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 SEQ ID 
                 SEQ ID 
                 SEQ ID 
                 SEQ ID 
                 SEQ ID 
                 SEQ ID 
                 SEQ ID 
               
               
                 nM of 
                 NO: 131 
                 NO: 132 
                 NO: 133 
                 NO: 134 
                 NO: 135 
                 NO: 136 
                 NO: 137 
               
               
                 peptide 
                 (% control) 
                 (% control) 
                 (% control) 
                 (% control) 
                 (% control) 
                 (% control) 
                 (% control) 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 30000 
                 30 
                 44 
                 42 
                 41 
                 16 
                 42 
                 56 
                 45 
                 29 
                 37 
                 26 
                 62 
                 27 
                 9 
               
               
                 10000 
                 16 
                 14 
                 49 
                 50 
                 24 
                 39 
                 60 
                 47 
                 43 
                 57 
                 34 
                 68 
                 23 
                 28 
               
               
                 300 
                 29 
                 42 
                 46 
                 44 
                 41 
                 56 
                 75 
                 68 
                 70 
                 87 
                 81 
                 84 
                 54 
                 77 
               
               
                 100 
                 49 
                 62 
                 59 
                 62 
                 75 
                 60 
                 89 
                 87 
                 107 
                 75 
                 98 
                 84 
                 68 
                 74 
               
               
                 30 
                 71 
                 68 
                 71 
                 89 
                 80 
                 68 
                 101 
                 76 
                 89 
                 90 
                 65 
                 84 
                 78 
                 94 
               
               
                 10 
                 74 
                 66 
                 54 
                 56 
                 77 
                 113 
                 105 
                 77 
                 104 
                 79 
                 80 
                 71 
                 100 
                 89 
               
               
                 3 
                 71 
                 85 
                 78 
                 75 
                 95 
                 79 
                 94 
                 92 
                 74 
                 67 
                 76 
                 98 
                 82 
                 97 
               
               
                 1 
                 85 
                 68 
                 67 
                 79 
                 96 
                 82 
                 128 
                 81 
                 84 
                 76 
                 71 
                 90 
                 80 
                 106 
               
               
                 0.3 
                 105 
                 81 
                 100 
                 71 
                 108 
                 78 
                 104 
                 85 
                 99 
                 72 
                 103 
                 70 
                 58 
                 92 
               
               
                 0.1 
                 97 
                 80 
                 73 
                 89 
                 78 
                 85 
                 80 
                 96 
                 63 
                 96 
                 67 
                 81 
                 72 
                 123 
               
               
                 0.1 
                 97 
                 94 
                 95 
                 92 
                 96 
                 101 
                 108 
                 75 
                 74 
                 85 
                 82 
                 94 
                 80 
                 82 
               
               
                 0.1 
                 96 
                 113 
                 117 
                 96 
                 87 
                 116 
                 138 
                 79 
                 129 
                 112 
                 116 
                 108 
                 103 
                 135 
               
               
                   
               
            
           
         
       
     
     The peptides generated in the Ala-, Lys- and Pro-scanning experiments are set forth below in table 17. 
     
       
         
           
               
             
               
                 TABLE 17 
               
             
            
               
                   
               
               
                 Peptides generated in Ala-, Lys- 
               
               
                 and Pro- scanning experiments 
               
            
           
           
               
               
            
               
                 Amino acid sequence 
                 Sequence identifier 
               
               
                   
               
               
                 A-I-K-W-E-Y-V-L-L-L-F-L-L 
                 SEQ ID NO: 81 
               
               
                   
               
               
                 G-I-K-W-E-Y-V-L-L-L-E-L-L 
                 SEQ ID NO: 82 
               
               
                   
               
               
                 A-G-K-W-E-Y-V-L-L-L-F-L-L 
                 SEQ ID NO: 83 
               
               
                   
               
               
                 A-I-G-W-E-Y-V-L-L-L-F-L-L 
                 SEQ ID NO: 109 
               
               
                   
               
               
                 A-I-K-G-E-Y-V-L-L-L-E-L-L 
                 SEQ ID NO: 110 
               
               
                   
               
               
                 A-I-K-W-G-Y-V-L-L-L-F-L-L 
                 SEQ ID NO: 84 
               
               
                   
               
               
                 A-I-K-W-E-G-V-L-L-L-F-L-L 
                 SEQ ID NO: 111 
               
               
                   
               
               
                 A-I-K-W-E-Y-G-L-L-L-F-L-L 
                 SEQ ID NO: 112 
               
               
                   
               
               
                 A-I-K-W-E-Y-V-L-L-L-F-G-L 
                 SEQ ID NO: 113 
               
               
                   
               
               
                 A-I-K-W-E-H-V-L-L-L-F-L-G 
                 SEQ ID NO: 114 
               
               
                   
               
               
                 A-I-K-W-E-Y-V-L-L-L-F-L-L 
                 SEQ ID NO: 85 
               
               
                   
               
               
                 A-I-K-W-E-Y-V-L-L-L-F-L-L 
                 SEQ ID NO: 86 
               
               
                   
               
               
                 A-A-K-W-E-Y-V-L-L-L-F-L-L 
                 SEQ ID NO: 87 
               
               
                   
               
               
                 A-I-A-W-E-Y-V-L-L-L-F-L-L 
                 SEQ ID NO: 88 
               
               
                   
               
               
                 A-I-K-A-E-Y-V-L-L-L-F-L-L 
                 SEQ ID NO: 89 
               
               
                   
               
               
                 A-I-K-W-A-Y-V-L-L-L-F-L-L 
                 SEQ ID NO: 90 
               
               
                   
               
               
                 A-I-K-W-E-A-V-L-L-L-F-L-L 
                 SEQ ID NO: 91 
               
               
                   
               
               
                 A-I-K-W-E-Y-A-L-L-L-F-L-L 
                 SEQ ID NO: 92 
               
               
                   
               
               
                 A-I-K-W-E-Y-V-A-L-L-F-L-L 
                 SEQ ID NO: 93 
               
               
                   
               
               
                 A-I-K-W-E-Y-V-L-A-L-F-L-L 
                 SEQ ID NO: 94 
               
               
                   
               
               
                 A-I-K-W-E-Y-V-L-L-A-E-L-L 
                 SEQ ID NO: 115 
               
               
                   
               
               
                 A-I-K-W-E-Y-V-L-L-L-A-L-L 
                 SEQ ID NO: 95 
               
               
                   
               
               
                 A-I-K-W-E-Y-V-L-L-L-F-A-L 
                 SEQ ID NO: 96 
               
               
                   
               
               
                 A-I-K-W-E-Y-V-L-L-L-F-L-A 
                 SEQ ID NO: 97 
               
               
                   
               
               
                 A-I-K-W-E-Y-V-L-L-L-F-L-L 
                 SEQ ID NO: 98 
               
               
                   
               
               
                 P-I-K-W-E-Y-V-L-L-L-F-L-L 
                 SEQ ID NO: 99 
               
               
                   
               
               
                 A-P-K-W-E-Y-V-L-L-L-F-L-L 
                 SEQ ID NO: 116 
               
               
                   
               
               
                 A-I-P-W-E-Y-V-L-L-L-F-L-L 
                 SEQ ID NO: 117 
               
               
                   
               
               
                 A-I-K-P-E-Y-V-L-L-L-F-L-L 
                 SEQ ID NO: 118 
               
               
                   
               
               
                 A-I-K-W-P-Y-V-L-L-L-F-L-L 
                 SEQ ID NO: 119 
               
               
                   
               
               
                 A-I-K-W-E-P-V-L-L-L-F-L-L 
                 SEQ ID NO: 120 
               
               
                   
               
               
                 A-I-K-W-E-Y-P-L-L-L-F-L-L 
                 SEQ ID NO: 121 
               
               
                   
               
               
                 A-I-K-W-E-Y-V-P-L-L-F-L-L 
                 SEQ ID NO: 122 
               
               
                   
               
               
                 A-I-K-W-E-Y-V-L-P-L-F-L-L 
                 SEQ ID NO: 123 
               
               
                   
               
               
                 A-I-K-W-E-Y-V-L-L-P-F-L-L 
                 SEQ ID NO: 124 
               
               
                   
               
               
                 A-I-K-W-E-Y-V-L-L-L-P-L-L 
                 SEQ ID NO: 125 
               
               
                   
               
               
                 A-I-K-W-E-Y-V-L-L-L-F-P-L 
                 SEQ ID NO: 126 
               
               
                   
               
               
                 A-I-K-W-E-Y-V-L-L-L-F-L-P 
                 SEQ ID NO: 127 
               
               
                   
               
               
                 A-I-K-W-E-Y-V-L-L-L-F-L-L 
                 SEQ ID NO: 100 
               
               
                   
               
               
                 K-I-K-W-E-Y-V-L-L-L-F-L-L 
                 SEQ ID NO: 101 
               
               
                   
               
               
                 A-K-K-W-E-Y-V-L-L-L-F-L-L 
                 SEQ ID NO: 102 
               
               
                   
               
               
                 A-I-K-W-E-Y-V-L-L-L-F-L-L 
                 SEQ ID NO: 103 
               
               
                   
               
               
                 A-I-K-K-E-Y-V-L-L-L-F-L-L 
                 SEQ ID NO: 128 
               
               
                   
               
               
                 A-I-K-W-K-Y-V-L-L-L-F-L-L 
                 SEQ ID NO: 129 
               
               
                   
               
               
                 A-I-K-W-E-K-V-L-L-L-F-L-L 
                 SEQ ID NO: 130 
               
               
                   
               
               
                 A-I-K-W-E-Y-K-L-L-L-F-L-L 
                 SEQ ID NO: 131 
               
               
                   
               
               
                 A-I-K-W-E-Y-V-K-L-L-F-L-L 
                 SEQ ID NO: 132 
               
               
                   
               
               
                 A-I-K-W-E-Y-V-L-K-L-F-L-L 
                 SEQ ID NO: 133 
               
               
                   
               
               
                 A-I-K-W-E-Y-V-L-L-K-F-L-L 
                 SEQ ID NO: 134 
               
               
                   
               
               
                 A-I-K-W-E-Y-V-L-L-L-K-L-L 
                 SEQ ID NO: 135 
               
               
                   
               
               
                 A-I-K-W-E-Y-V-L-L-L-F-K-L 
                 SEQ ID NO: 136 
               
               
                   
               
               
                 A-I-K-W-E-Y-V-L-L-L-F-L-K 
                 SEQ ID NO: 137 
               
               
                   
               
            
           
         
       
     
     Taken together, the scanning data, establish that the amino terminal segment (AIKWE) (SEQ ID NO: 139) was more tolerant to substitutions whereas the carboxy terminal hydrophobic segment was less so. The potency was contributed collectively by many residues (as seen in alanine scanning). Peptide backbone contortion (as in proline scanning) or conformational de-constraining (as in glycine scanning) was not well tolerated. Perturbing the hydrophobic character in the carboxy terminal segment is also detrimental to activity (as seen with lysine scanning). 
     Example 3 
     Steps of HCVpp Entry Affected by the Peptide 
     To identify if the peptides of the invention bind to the cells and therefore inhibit entry, anti-CD81 antibody or peptide (SEQ ID NO: 77) was tested at four conditions:
         (A) peptide or anti-CD81 antibody was pre-incubated with cells and virus separately, cells were washed and virus together with peptide was added;   (B) peptide or anti-CD81 antibody was pre-incubated with virus only first and then virus together with peptide was added to the cells;   (C) peptide or anti-CD81 antibody was preincubated with cells only and washed off, and then virus was added; and   (D) same as C except that virus was washed off after 1 hour of incubation.       

     Realizing that during virus incubation, the pre-bond peptide or antibody could dissociate from the cells and therefore lose the effects on HCVpp entry, virus was removed at time points from 15 minutes to 4 hours and we compared the inhibition effects to that from leaving viruses on until harvest for luciferase. As shown in the data of table 18, when virus was removed at earlier time points, stronger inhibition was observed compared to leaving virus on until harvest. 
     
       
         
           
               
             
               
                 TABLE 18 
               
             
            
               
                   
               
               
                 Results of time course wherein virus was removed at various points.* 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
            
               
                 anti-CD81 
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 ug/ml 
                 5 min 
                 15 min 
                 30 min 
                 1 hr 
                 2 hr 
                 3 hr 
                 4 hr 
                 leaving on 
                 no wash off 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 10 
                 63 
                 60 
                 19 
                 29 
                 21 
                 25 
                 25 
                 35 
                 31 
                 67 
                 45 
                 48 
                 61 
                 88 
                 29 
                 73 
                 0 
                 1 
               
               
                 3.3333 
                 54 
                 27 
                 34 
                 41 
                 36 
                 33 
                 27 
                 34 
                 32 
                 59 
                 54 
                 45 
                 58 
                 65 
                 61 
                 73 
                 4 
                 3 
               
               
                 1.1111 
                 36 
                 56 
                 87 
                 57 
                 25 
                 46 
                 11 
                 61 
                 51 
                 56 
                 63 
                 63 
                 72 
                 90 
                 54 
                 83 
                 6 
                 2 
               
               
                 0.3704 
                 68 
                 98 
                 55 
                 59 
                 75 
                 71 
                 27 
                 43 
                 61 
                 86 
                 89 
                 71 
                 76 
                 112 
                 67 
                 95 
                 22 
                 22 
               
               
                 0.1235 
                 25 
                 59 
                 39 
                 33 
                 50 
                 32 
                 39 
                 21 
                 45 
                 42 
                 66 
                 52 
                 50 
                 41 
                 74 
                 98 
                 99 
                 122 
               
               
                 0.0412 
                 22 
                 27 
                 69 
                 37 
                 89 
                 86 
                 52 
                 49 
                 53 
                 78 
                 58 
                 69 
                 62 
                 51 
                 72 
                 111 
                 88 
                 101 
               
               
                 0.0137 
                 36 
                 56 
                 79 
                 64 
                 71 
                 93 
                 33 
                 49 
                 60 
                 64 
                 62 
                 87 
                 65 
                 74 
                 69 
                 110 
                 106 
                 124 
               
               
                 0.0046 
                 85 
                 27 
                 55 
                 66 
                 61 
                 72 
                 65 
                 66 
                 57 
                 73 
                 71 
                 87 
                 65 
                 53 
                 71 
                 112 
                 84 
                 97 
               
               
                 0.0015 
                 83 
                 67 
                 142 
                 104 
                 109 
                 122 
                 72 
                 71 
                 87 
                 79 
                 103 
                 91 
                 99 
                 104 
                 80 
                 118 
                 117 
                 97 
               
               
                 0.0005 
                 127 
                 117 
                 68 
                 74 
                 75 
                 92 
                 88 
                 74 
                 63 
                 91 
                 87 
                 91 
                 92 
                 79 
                 77 
                 114 
                 94 
                 92 
               
               
                 0.0002 
                 80 
                 79 
                 89 
                 75 
                 90 
                 120 
                 145 
                 78 
                 119 
                 119 
                 82 
                 108 
                 126 
                 97 
                 74 
                 108 
               
               
                 0.0002 
                 95 
                 145 
                 138 
                 98 
                 89 
                 101 
                 94 
                 83 
                 70 
                 92 
                 100 
                 110 
                 94 
                 83 
                 93 
                 124 
               
               
                   
               
               
                 *Numbers represent the viral entry observed at each time point and antibody concentration tested as a percentage of the uninhibited control 
               
            
           
         
       
     
     The majority of difference seen before the 4-hour time-point is in line with the model wherein most of the entry events occur during the first four hours (data not shown). As expected, the RLU signal was reduced at earlier time points and lead to higher variation of the assay. In general, when anti-CD81 antibody was removed, the earlier removal of virus seemed to correlate with a greater inhibition, indicating dissociation of anti-CD81 antibody from cells. In anticipating similar phenomena might exist with the peptide, we applied the one hour virus incubation in the following studies. In tables 19-22, condition D was identical to condition C except that virus was removed after 1 hour of incubation. The dose-response curves from condition A superimposed that from condition B, and little inhibition was observed at condition C, indicating the pre-bond antibody or peptide on cell offered no advantages in blocking HCVpp entry, or alternatively, the affinity of peptide and antibody to cells is low and can dissociate from cells rather quickly. The experiments performed under condition D suggested that the latter might be the case, in that the earlier the infection was terminated, there seemed to be a greater inhibition effect from the prebond peptide and antibody. Anti-CD81 antibody binds to CD81 expressed on the cells and therefore blocks HCVpp entry. Comparing to anti-CD81 antibody, the peptide exhibited more inhibition when pre-incubated with cells at 37° C. and 4° C. in the wash-off experiment, indicating that it most likely interacted with the cells and inhibited HCVpp entry. 
     The data in tables 19 and 20 were generated in assays conducted at 37° C. The date generated in tables 21 and 22 were generated in assays conducted at 4° C. The numbers in each table (19-22) represent the luciferase units observed in the entry assay under each indicated condition. 
     
       
         
           
               
             
               
                 TABLE 19 
               
             
            
               
                   
               
               
                 Wash off study of anti-CD-81 antibody at 37° C. 
               
            
           
           
               
               
               
               
               
            
               
                 anti-CD81 
                   
                   
                   
                   
               
               
                 antibody 
               
               
                 (ug/ml) 
                 condition A 
                 condition B 
                 condition C 
                 condition D 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 10 
                 179 
                 609 
                 885 
                 1378 
                 35920 
                 35648 
                 5002 
                 1964 
               
               
                 3.333333 
                 1923 
                 1259 
                 1481 
                 1643 
                 39146 
                 32572 
                 2063 
                 3976 
               
               
                 1.111111 
                 2437 
                 719 
                 3672 
                 1402 
                 35842 
                 33312 
                 3158 
                 2386 
               
               
                 0.3703704 
                 9829 
                 9696 
                 9224 
                 11247 
                 39546 
                 36517 
                 1192 
                 3805 
               
               
                 0.1234568 
                 43590 
                 53450 
                 53230 
                 41923 
                 41983 
                 46677 
                 3801 
                 8524 
               
               
                 0.04115226 
                 38615 
                 44249 
                 45687 
                 40315 
                 51423 
                 45565 
                 2736 
                 4057 
               
               
                 0.01371742 
                 46405 
                 54468 
                 38470 
                 48976 
                 38356 
                 42778 
                 2755 
                 5184 
               
               
                 0.004572474 
                 36968 
                 42764 
                 46670 
                 44647 
                 38239 
                 42076 
                 3899 
                 4580 
               
               
                 0.004572474 
                 51599 
                 42409 
                 56802 
                 46508 
                 41564 
                 49023 
                 3482 
                 7151 
               
               
                 0.004572474 
                 41187 
                 40579 
                 34004 
                 46112 
                 38135 
                 44170 
                 5511 
                 6649 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 20 
               
             
            
               
                   
               
               
                 Wash off study of peptide (SEQ ID NO: 77) at 37° C. 
               
            
           
           
               
               
               
               
               
            
               
                 peptide V-2b 
                   
                   
                   
                   
               
               
                 (SEQ ID NO: 
               
               
                 77) (ug/ml) 
                 condition A 
                 condition B 
                 condition C 
                 condition D 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 100.0000 
                 9216 
                 7419 
                 8074 
                 4093 
                 19088 
                 14073 
                 780 
                 1531 
               
               
                 33.3333 
                 6467 
                 6356 
                 7146 
                 4501 
                 23383 
                 19309 
                 2351 
                 2058 
               
               
                 11.1111 
                 12402 
                 6768 
                 10212 
                 6902 
                 28818 
                 33022 
                 3302 
                 3259 
               
               
                 3.7037 
                 15025 
                 10613 
                 15213 
                 12233 
                 31857 
                 32265 
                 2974 
                 3707 
               
               
                 1.2346 
                 21301 
                 21733 
                 25204 
                 14452 
                 36450 
                 40467 
                 2078 
                 4828 
               
               
                 0.4115 
                 28106 
                 25559 
                 26979 
                 31819 
                 40225 
                 43467 
                 3257 
                 2555 
               
               
                 0.1372 
                 44159 
                 41959 
                 43468 
                 36136 
                 34241 
                 44163 
                 2443 
                 4834 
               
               
                 0.0457 
                 50460 
                 53231 
                 47929 
                 53377 
                 36956 
                 46680 
                 3531 
                 2785 
               
               
                 0.0046 
                 74772 
                 76125 
                 65028 
                 60343 
                 40529 
                 45271 
                 4566 
                 6407 
               
               
                 0.0046 
                 57485 
                 58523 
                 57349 
                 51858 
                 37116 
                 32831 
                 3984 
                 2714 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 21 
               
             
            
               
                   
               
               
                 Wash off study of anti-CD-81 antibody at 4° C. 
               
            
           
           
               
               
               
               
            
               
                 anti-CD81 
                   
                   
                   
               
               
                 antibody 
               
               
                 (ug/ml) 
                 condition A 
                 condition B 
                 condition C 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 10 
                 42 
                 242 
                 78 
                 37 
                 6720 
                 8027 
               
               
                 3.3333 
                 14 
                 135 
                 382 
                 470 
                 11036 
                 10783 
               
               
                 1.1111 
                 1733 
                 253 
                 1815 
                 706 
                 10112 
                 11783 
               
               
                 0.3704 
                 1885 
                 1046 
                 2988 
                 1939 
                 9220 
                 18281 
               
               
                 0.1235 
                 6160 
                 5063 
                 7111 
                 5662 
                 11651 
                 11051 
               
               
                 0.0412 
                 11764 
                 8052 
                 16527 
                 11566 
                 10723 
                 11422 
               
               
                 0.0137 
                 12944 
                 10622 
                 13979 
                 15817 
                 7207 
                 12271 
               
               
                 0.0046 
                 10693 
                 11365 
                 12812 
                 11119 
                 11552 
                 15524 
               
               
                 0.0046 
                 9969 
                 11238 
                 15082 
                 15072 
                 12008 
                 9342 
               
               
                 0.0046 
                 15243 
                 12178 
                 10078 
                 12548 
                 8921 
                 9666 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 22 
               
             
            
               
                   
               
               
                 Wash off study of peptide (SEQ ID NO: 77) at 4° C. 
               
            
           
           
               
               
               
               
            
               
                 peptide V-2b 
                   
                   
                   
               
               
                 (SEQ ID No: 
               
               
                 77) (ug/ml) 
                 condition A 
                 condition B 
                 condition C 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 100 
                 1924 
                 1845 
                 1233 
                 2486 
                 5118 
                 8821 
               
               
                 33.3333 
                 1677 
                 2383 
                 2900 
                 1914 
                 8294 
                 8104 
               
               
                 11.1111 
                 2833 
                 2954 
                 996 
                 2597 
                 7352 
                 4725 
               
               
                 3.7037 
                 2824 
                 3255 
                 3059 
                 3424 
                 9414 
                 8570 
               
               
                 1.2346 
                 3584 
                 5974 
                 5542 
                 4382 
                 6131 
                 6853 
               
               
                 0.4115 
                 5517 
                 5574 
                 4724 
                 3648 
                 9027 
                 11381 
               
               
                 0.1372 
                 5745 
                 7826 
                 7670 
                 6880 
                 9444 
                 10124 
               
               
                 0.0457 
                 7498 
                 7299 
                 6703 
                 9954 
                 16101 
                 13757 
               
               
                 0.0046 
                 22435 
                 18765 
                 26860 
                 23215 
                 13903 
                 13795 
               
               
                 0.0046 
                 17613 
                 22306 
                 23633 
                 21213 
                 14095 
                 10535 
               
               
                   
               
            
           
         
       
     
     In an effort to determine if the peptides of the invention inhibited HCVpp entry at attachment or post-attachment steps, the peptide (sEQ ID NO: 77) was pre-incubated with cells at 4° C. followed by incubation with HCV pseudoparticles at 4° C. The entry process was allowed to complete after the cells were washed and incubated at 37° C. for 72 hours. If the peptide blocked or interfered with the attachment, few HCVpp particles should bind to the cells and lead to reduced luciferase signal. The peptide had approximately 50% inhibition whereas the anti-CD81 antibody inhibited entry by 20%. Alternatively, an explanation could be that the cell-associated peptide or antibody had no effects on virus attachment, but rather inhibit post-attachment steps, e.g. fusion. When we allowed the HCV pseudoparticles to attach first at 4° C., a nonpermissive temperature for fusion, and added the peptide or anti-CD81 antibody when post-attachment events occurred, anti-CD81 antibody almost inhibited entry by 100%, whereas, the peptide inhibited by approximately 80%. Our observation that anti-CD81 antibody inhibited HCVpp entry at a post-attachment step is consistent with published results (Cormier et al, Proc. Natl. Acad. Sci. 101:7270-7274). Our data also indicates that the peptide largely inhibits a post-attachment step. 
     The incubation scheme for the fusion/attachment experiments is summarized as follows: 
     
       
         
         
             
             
         
       
     
     
       
         
           
               
             
               
                 TABLE 23 
               
               
                   
               
               
                 Data generated in fusion/attachment experiments 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
            
               
                   
                   
                 average 
                   
               
               
                 RLU 
                 V-2b (SEQ ID NO: 77) 
                 (peptide) 
                 anti-CD81 antibody 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 A + P 
                 527 
                 1541 
                 520 
                 863 
                 13 
                 10 
               
               
                 A 
                 5196 
                 7987 
                 4644 
                 5942 
                 10851 
                 6692 
               
               
                 P 
                 1984 
                 2412 
                 545 
                 1647 
                 13 
                 15 
               
               
                 Noinh. 
                 13359 
                 14364 
                 17778 
                 15167 
                 13164 
                 13994 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                 average 
                 % control 
                 % control anti- 
               
               
                   
                 anti-CD81 antibody 
                 (antibody) 
                 peptide 
                 CD81 antibody 
               
               
                   
               
               
                 A + P 
                 12 
                 12 
                 6 
                 0 
               
               
                 A 
                 9662 
                 9068 
                 39 
                 82 
               
               
                 P 
                 714 
                 247 
                 11 
                 0 
               
               
                 Noinh. 
                 14957 
                 14038 
                 100 
                 100 
               
               
                   
               
               
                 A = attachment; P = post attachment; Noinh = no inhibition 
               
            
           
         
       
     
     The present invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the appended claims. 
     Patents, patent applications, publications, product descriptions, and protocols are cited throughout this application, the disclosures of which are incorporated herein by reference in their entireties for all purposes.