ACID STABLE BACKBONE MODIFIED END-BLOCKED NUCLEIC ACIDS AND THERAPEUTIC USES THEREOF

Abstract: The present invention provides end-blocked nucleic acids, e.g., 2'-O-R, 2'-O-R-O-R, 3'-O-R, and 3'-O-R-O-R oligonucleotides, that exhibit significant low pH stability, nuclease resistance and optionally antibacterial properties. These low toxicity, highly specific, acid stable, end-blocked nucleic acids represent a novel and improved oligonucleotide structure for therapeutic treatments of diseases. The 3' and 5' acid stable, exonuclease resistant polymers of the invention are shown here to provide antibacterial effects when applied in vivo, e.g., applied topically to skin with actual sites of infection on dogs and humans.

Description: ACID STABLE BACKBONE MODIFIED END-BLOCKED NUCLEIC ACIDS AND THERAPEUΗC USES THEREOF FIELD OF THE INVENTION The invention relates generally to the field of modified nucleic acids and more specifically to nucleic acids stable in acidic conditions. BACKGROUND TO THE INVENTION The use of antisense oligonucleotides has emerged as a powerful new approach for the treatment of diseases. The preponderance of the work to date has focused on the use of antisense oligonucleotides as antiviral agents and as anticancer agents (Wickstrom, F., Ed., Prospects for Antisense Nucleic Acid Therapy of Cancer and AIDS, New York: Wiley-Liss, 1991; Crooke, ST. and Lebleu, B., Eds., Antisense Research and Applications, Boca Raton: CRC Press, 1993, pp. 154-182; Baserga, R. and Denhardt, D.T., 1992, Antisense Strategies, New York: The New York Academy of Sciences, Vol. 660; Murray, J.A.H., Ed., Antisense RNA and DNA, New York: Wiley-Liss, 1993; Agrawal et al., Proc. Natl. Acad. Sci. USA 85:7079-7083 (1988), Zamecnik et al., Proc. Natl. Acad. Sci. USA 83:4143-4146 (1986)). A large variety of different chemistries has been used to construct antisense oligonucleotides for such in vivo uses. The goal in each case has been to construct oligonucleotides that are both resistant to nucleases so they will be stable in vivo and that are able to bind tightly and selectively to the appropriate RNA or DNA to inhibit expression of the targeted gene. The backbone design favored by most groups pursuing nuclease-resistant antisense therapeutics relies on an RNase H-based mechanism with DNA analogues capable of being recognized by RNase H. Consequently, there has been limited interest in oligonucleotides composed solely of groups that are not recognized by RNase H, such as 2'-0-methyl RNA. Concerns about exonuclease stability of 2'-0-methyl RNA oligonucleotides has further limited interest in their therapeutic use (Shibahara et al. , Nucleic Acids Res. 17:239, 1989). In fact, the relatively low exonuclease resistance of phosphodiester 2'-0-methyls has led some to conclude that, although the 2'-0-methyl(phosphodiester) derivatives are more resistant to degradation by nucleases than DNA, neither DNA nor 2'-0-methyl RNA maintains sufficient stability for antisense applications (De Mesmaeker et al., Acc. Chem. Res. 28:366-374 (1995)). In addition, a general limitation on the therapeutic use of oligonucleotides has been their poor bioavailability. Oral bioavailability of oligonucleotides can be affected by acid degradation in the gut, enzymatic cleavage in the intestines, poor intestinal absorption and liver first pass effects (Hughes et al., Pharmaceutical Research 12:817, 1995). Nucleic acids are sensitive to acidic conditions which can cause depurination and cleavage of the DNA or RNA backbone. Exposure of nucleic acids for as short a time as 10 minutes at room temperature at a pH of 1-2 (the average pH of the stomach) will cause some depurination, which may lead to hydrolysis of the nucleic acid at the sites of depurination. For instance, Crooke reported very limited (<5%) bioavailability of orally introduced oligonucleotides in rodents (S. Crooke, in. Antisense Oligonucleotides and Antisense RNA: Novel Pharmacological and Therapeutic Agents, B. Weiss, Ed., CRC Press, Boca Raton, FL, p. 17, 1997). There is a need for antisense oligonucleotides and other modified nucleic acid sequences that have increased bioavailability. Thus, there is a need for nucleic acid sequences that are more resistant to acid degradation in vivo, but that retain their ability to modulate gene expression. SUMMARY OF THE INVENTION The present invention provides end-blocked acid resistant nucleic acids, e.g., end-blocked 2'- modified or 3 '-modified oligonucleotides, that exhibit substantial acid resistance, substantial resistance to nuclease degradation, and binding specificity both in vivo and in vitro. These low toxicity, highly specific, acid stable, end-blocked nucleic acids represent an improved nucleic acid structure for therapeutic treatments of diseases. The 3' and/or 5' acid stable, nuclease resistant ends provide unique properties that allow modified nucleic acids of the invention to have improved bioavailability for therapeutic uses particularly when administered in an oral dosage form. In one embodiment, the invention provides therapeutic uses of end-blocked acid stable nucleic acids as antibacterial agents. Specifically, the end-blocked nucleic acids of the invention are effective to treat or prevent diseases involving viral infection, bacterial infection, inflammatory diseases, cancer, fungal infections, etc. The substantial acid and nuclease resistance allows the nucleic acids to have increased bioavailability while maintaining their ability to bind to their target sequences with specificity. These nucleic acids are stable for at least one hour at 37 °C in a pH range of 1 to 12. Moreover, the nucleic acids can be additionally protonated to simultaneously treat or prevent a bacterial infection. Above a pH of 7.0 the oligonucleotides, although stable, generally do not have the same antibiotic effects. Thus, modified nucleic acid compositions of the invention are preferably formulated using a low pH carrier composition. The invention further provides the use of an end-blocked acid stable nucleic acid molecule in conjunction with an acceptable pharmaceutical carrier as medicinal compositions for the treatment of disease in animals, and more preferably mammals, including humans. The present invention also provides methods to chemically modify nucleic acids to confer substantial acid resistance and substantial nuclease resistance. The resulting end-blocked nucleic acids can be used to treat animals, including humans, having a disease that is treatable by the modulation of gene expression. It is an advantage of the nucleic acids of the invention that the acid stable ends confer an improved stability on the modified nucleic acids in an acidic environment (e.g., the stomach with a pH of 1 to 2), and thus increased bioavailability in vivo. It is another advantage of the nucleic acids of the invention that they bind with specificity to target sequences in vivo and in vitro. It is another advantage of the invention that the end-blocked nucleic acids are non-toxic to a subject treated with the modified nucleic acids. The modified nucleic acids of the present invention, e.g., 2'-modified and 3'-modified oligonucleotides, do not display side effects commonly caused by therapeutic administration of regular polyanionic oligonucleotides, such as increased binding to serum and other proteins, stimulation of serum transaminases, decreases in platelet counts, and the like. It is yet another advantage that the acid stable ends confer an improved stability on the modified nucleic acids in the acid environments of lysosomal vesicles in macrophages and neutrophils. It is yet another advantage that the modifications of the invention allow the preparation of stable protonated nucleic acids, including oligonucleotides, for antibacterial use. It is a further advantage that the nucleic acids of the present invention are readily encapsulated in charged liposomes. It is an object of the invention that the nucleic acids and low pH formulations of such nucleic acids can be used in a variety of antibacterial applications, such as sterilization of surgical instruments, use in antibacterial products such as lotions and soaps, and the like. These and other objects, advantages, and features of the invention will become apparent to those skilled in the art upon reading the details of the nucleic acids and uses thereof as more fully described below. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 illustrates the chemical structure of a nucleotide used in the nucleic acids of the invention having a 2'-0-methyl group. Figure 2 illustrates the chemical structure of a nucleotide used in the nucleic acids of the invention having a 2'-methoxy ethoxy group. Figure 3 illustrates the chemical structure of a nucleotide used in the nucleic acids of the invention having a 2'-fluorine. Figure 4 illustrates the chemical structure of a sulfur nucleotide used in the nucleic acids of the invention having a 2'-0-methyl group. Figure 5 illustrates the chemical structure of a phosphoramidate nucleotide used in the nucleic acids of the invention having a 2'-0-methyl group. Figure 6 illustrates two monomers of the preferred embodiment of the invention. Figure 7 illustrates one example of an acid stable, end-blocked polymer of the invention. Figure 8 illustrates the preferred embodiment of an acid stable, end-blocked polymer of the invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS It is to be understood that this invention is not limited to the particular methodology, protocols, cell lines, animal species or genera, constructs, and reagents described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention which will be limited only by the appended claims . It must be noted that as used herein and in the appended claims, the singular forms "a", "and", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "bacteria" may include a plurality of bacterial species and "an oligonucleotide" may encompass a plurality of oligonucleotides and equivalents thereof known to those skilled in the art, and so forth. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this invention belongs. Although any methods, devices and materials similar or equivalent to those described herein can be used in the practice or testing of the invention, the preferred methods, devices and materials are now described. All publications mentioned are incorporated herein by reference for the purpose of describing and disclosing, for example, the cell lines, constructs, and methodologies that are described in the publications which might be used in connection with the presently described invention. The publications discussed above and throughout the text are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the inventors are not entitled to antedate such disclosure by virtue of prior invention. DEFINITIONS The terms "nucleic acid" and "nucleic acid molecule" as used interchangeably herein, refer to a molecule comprised of nucleotides, i.e., ribonucleotides, deoxyribonucleotides, or both. The term includes monomers and polymers of ribonucleotides and deoxyribonucleotides, with the ribonucleotide and/or deoxyribonucleotides being connected together, in the case of the polymers, via 5' to 3' linkages. However, linkages may include any of the linkages known in the nucleic acid synthesis art including, for example, nucleic acids comprising 5' to 2' linkages. The nucleotides used in the nucleic acid molecule may be naturally occurring or may be synthetically produced analogues that are capable of forming base-pair relationships with naturally occurring base pairs. Examples of non-naturally occurring bases that are capable of forming base-pairing relationships include, but are not limited to, aza and deaza pyrimidine analogues, aza and deaza purine analogues, and other heterocyclic base analogues, wherein one or more of the carbon and nitrogen atoms of the purine and pyrimidine rings have been substituted by heteroatoms, e.g., oxygen, sulfur, selenium, phosphorus, and the like. The term "oligonucleotide" as used herein refers to a nucleic acid molecule comprising from about 1 to about 100 nucleotides, more preferably from 1 to 80 nucleotides, and even more preferably from about 4 to about 35 nucleotides. The terms "modified oligonucleotide" and "modified nucleic acid molecule" as used herein refer to nucleic acids, including oligonucleotides, with one or more chemical modifications at the molecular level of the natural molecular structures of all or any of the nucleic acid bases, sugar moieties, intemucleoside phosphate linkages, as well as molecules having added substituents, such as diamines, cholesteryl or other lipophilic groups, or a combination of modifications at these sites. The chemical modifications provide characteristics including (1) enhanced acid stability; (2) enhanced nuclease resistance; and (3) enhanced ability to permeate cells — all relative to natural nucleic acids. The intemucleoside phosphate linkages can be phosphodiester, phosphotriester, phosphoramidate, siloxane, carbonate, carboxymethylester, acetamidate, carbamate, thioether, bridged phosphoramidate, bridged methylene phosphonate, phosphorothioate, methylphosphonate, phosphorodithioate, bridged phosphorothioate and/or sulfone internucleotide linkages, or 3 -3', 5'-2' or 5 -5' linkages, and combinations of such similar linkages (to produce mixed backbone modified oligonucleotides). The modifications can be internal (single or repeated) or at the end(s) of the oligonucleotide molecule and can include additions to the molecule of the intemucleoside phosphate linkages, such as cholesteryl, diamine compounds with varying numbers of carbon residues between amino groups and terminal ribose, deoxyribose and phosphate modifications which cleave or cross-link to the opposite chains or to associated enzymes or other proteins. Electrophilic groups such as ribose-dialdehyde could covalently link with an epsilon amino group of the lysyl-residue of such a protein. A nucleophilic group such as tt-ethylmaleimide tethered to an oligomer could covalently attach to the 5' end of an mRNA or to another electrophilic site. The term modified oligonucleotides also includes oligonucleotides comprising modifications to the sugar moieties such as 2'-substituted ribonucleotides, or deoxyribonucleotide monomers, any of which are connected together via 5' to 3' linkages. Modified oligonucleotides may also be comprised of PNA or morpholino modified backbones where target specificity of the sequence is maintained. The term "nucleic acid backbone" as used herein refers to the structure of the chemical moiety linking nucleotides in a molecule. This may include stmctures formed from any and all means of chemically linking nucleotides. A modified backbone as used herein includes modifications to the chemical linkage between nucleotides, as well as other modifications that may be used to enhance stability and affinity, such as modifications to the sugar structure. For example an a-anomer of deoxyribose may be used, where the base is inverted with respect to the natural b-anomer. In a preferred embodiment, the 2'-OH or 3'-OH of the sugar group may be altered, for example, to 2 -R, 2'- O-R, 3'-0-R, 2 -O-R-O-R and 3'-0-R-0-R, which provides resistance to degradation without compromising affinity. The "R" group may be any chemical moiety that does not compromise the structural integrity of the nucleotide molecule, for example an alkyl group or a halogen molecule, e.g., fluorine or chlorine. The term "acidification" and "protonation/acidification" as used interchangeably herein refers to the process by which protons (or positive hydrogen ions) are added to proton acceptor sites on a nucleic acid. The proton acceptor sites include the amine groups on the base stmctures of the nucleic acid and the phosphate of the phosphodiester linkages. As the pH is decreased, the number of these acceptor sites which are protonated increases, resulting in a more highly protonated/acidified nucleic acid. The term "protonated/acidified nucleic acid" refers to a nucleic acid that, when dissolved in water at a concentration of approximately 16 A 260 per ml, has a pH lower than physiological pH, i.e., lower than approximately pH 7. Modified nucleic acids, nuclease-resistant nucleic acids, and antisense nucleic acids may all be encompassed by this definition. Generally, nucleic acids are protonated/acidified by adding protons to the reactive sites on a nucleic acid via exposure of the nucleic acid to an acidic environment, e.g., exposure to an organic or mineral acid. Other modifications that will decrease the pH of the nucleic acid can also be used and are intended to be encompassed by this term. The term "end-blocked" as used herein refers to a nucleic acid with a chemical modification at the molecular level that prevents the degradation of selected nucleotides, e.g., by nuclease action. This chemical modification is positioned such that it protects the integral portion of the nucleic acid, for example the coding region of an antisense oligonucleotide. An end block may be a 3' end block or a 5' end block. For example, a 3' end block may be at the 3 '-most position of the molecule, or it may be internal to the 3' ends, provided it is 3' of the integral sequences of the nucleic acid. The term "substantially nuclease resistant" refers to nucleic acids that are resistant to nuclease degradation, as compared to naturally occurring or unmodified nucleic acids. Modified nucleic acids of the invention are at least 1.25 times more resistant to nuclease degradation than their unmodified counterpart, more preferably at least 2 times more resistant, even more preferably at least 5 times more resistant, and most preferably at least 10 times more resistant than their unmodified counterpart. Such substantially nuclease resistant nucleic acids include, but are not limited to, nucleic acids with modified backbones such as phosphorothioates, methylphosphonates, ethylphosphotriesters, 2'-0- methylphosphorothioates, 3'-0-methylphosphorothioates, 2'-0-methyl-p-ethoxy ribonucleotides, 3'-0- methyl-p-ethoxy ribonucleotides, 2'-0-alkyls, 3'-0-alkyls, 2'-0-alkyl-n(0-alkyl), 3'-0-alkyl-n(0- alkyl), 2'-fluoros, 3'-fluoros, 3'-deoxy-erythropentofuranosyls, 3'-deoxy-erythropentofuranosyls, 2'-0- methyl ribonucleosides, 3'-0-methyl ribonucleosides, methyl carbamates, methyl carbonates, inverted bases (e.g., inverted T's), or chimeric versions of these backbones. The term "substantially acid resistant" as used herein refers to nucleic acids that are resistant to acid degradation as compared to unmodified nucleic acids. Typically, the relative acid resistance of a nucleic acid will be measured by comparing the percent degradation of a resistant nucleic acid with the percent degradation of its unmodified counterpart (i.e., a corresponding nucleic acid with "normal" backbone, bases, and phosphodiester linkages). A nucleic acid that is acid resistant is preferably at least 1.5 times more resistant to acid degradation, at least 2 times more resistant, even more preferably at least 5 times more resistant, and most preferably at least 10 times more resistant than their unmodified counterpart. The term "LD 50 " as used herein is the dose of an active substance that will result in 50 per cent lethality in all treated experimental animals. Although this usually refers to invasive administration, such as oral, parenteral, and the like, it may also apply to toxicity using less invasive methods of administration, such as topical applications of the active substance. The term "alkyl" as used herein refers to a branched or unbranched saturated hydrocarbon chain containing 1-6 carbon atoms, such as methyl, ethyl, propyl, tert-butyl, n-hexyl and the like. The terms "treatment", "treating" and the like are used herein to generally mean obtaining a desired pharmacologic and/or physiologic effect. The effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and/or may be therapeutic in terms of a partial or complete cure for a disease and/or adverse effect attributable to the disease. "Treatment" as used herein covers any treatment of a disease in a mammal, particularly a human, and includes: (a) preventing a disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting a disease, i.e., arresting its development; or (c) relieving a disease, i.e., ameliorating and/or causing regression of the disease. The invention is generally directed toward treating patients by the administration of a nucleic acid sequence that will modulate expression of an endogenous gene in vivo. By "therapeutically effective amount" is meant a nontoxic but sufficient amount of a compound to provide the desired therapeutic effect, in the present case, that dose of modified nucleic acid which will be effective in relieving, ameliorating, or preventing symptoms of the condition or disease being treated. THE INVENTION IN GENERAL The present invention provides nucleic acids modified to have at least one acid resistant, exonuclease resistant block to decrease the exonuclease sensitivity of the molecule as compared to an unmodified or naturally occurring nucleic acid. In particular, the addition of a chemical moiety replacing the H+ at the 2' site on the sugar molecule, e.g., a 2'-R, 2'-0-R, or 2'-0-R-0-R, enhances the acid stability of the molecule, converting an acid-sensitive molecule into an acid stable construct. See Figures 1-5. Examples of end-blocked, modified monomers of the invention are shown in Figure 6. Preferably, an exonuclease resistant block is added to the 3' or, preferably, both the 3' and 5' ends of the oligonucleotides. See Figures 7-8. The 3' end of the molecule optionally will have both a derivative molecule at either the 2' or 3' position, and an end-block (e.g., a butyl or a butanol) at the other position. See, for example, Figure 8, which has a 3'-OR group and a 2' butanol blocking group at the 3' end of the molecule and a butyl blocking group at the 5' end of the molecule. The resulting end-blocked nucleic acids of the invention are non-toxic, acid resistant, exonuclease resistant, endonuclease resistant, and bind tightly to their RNA or DNA targets. They have proved to be excellent antisense agents in a variety of in vivo systems and have shown good therapeutic activity. In addition, these molecules are stable when protonated, and have the properties of stable-protonated antisense oligonucleotides outlined below. When the nucleic acids of the invention are modified as described herein to provide acid stability, the modification confers several desirable qualities as indicated below: 1. Oligonucleotides of the invention are stable to the environment found in the stomach and in lysosomal vesicles found in macrophages and neutrophils; 2. Oligonucleotides of the invention are stable when exposed to a pH of 1-2, allowing for protonation of the oligonucleotides; and 3. Protonated oligonucleotides of the invention have several unique features, including: protonated oligonucleotides are excellent anti-bacterial agents; protonated oligonucleotides are taken up better by cells; protonated oligonucleotides can be readily encapsulated in anionic liposomes; and protonated oligonucleotides do not trigger the toxic effects that are often seen with polyanionic oligonucleotides in vivo, i.e., prolongation of coagulation, decreases in platelet counts, activation of serum complement, increases in semm transaminases and the like. Various modifications of nucleic acids (contemplated by those skilled in the art upon reading this disclosure) which result in characteristics 1-3 are intended to be encompassed by the present invention. The invention encompasses nucleic acids chemically modified to have a pH resistance of 0.01 to 7.0, allowing such molecules to retain their structural integrities in acidic environments such as in the stomach. In a preferred embodiment, the nucleic acids of the invention are 2'-R, 2'-0-R, 3'-0-R, 2'-0-R-0-R and 3'-0-R-0-R oligonucleotides which exhibit significant acid resistance in solutions with pH as low as 0-1 even at 37° C. Acid stability of this first component coupled with the introduction of 3' or 3' and 5' acid stable, exonuclease resistant ends, confer several unique properties on such oligonucleotides. These low toxicity, highly specific, acid stable, end-blocked 2 -R, 2'-0-R, 3'-0-R, 2'-0-R-0-R and 3'-0-R-0-R oligonucleotides represent a novel and improved oligonucleotide structure for therapeutic treatments of diseases . Typically, the relative nuclease resistance of a nucleic acid can be measured by comparing the percent digestion of a resistant nucleic acid with the percent digestion of its unmodified counterpart (i.e., a corresponding nucleic acid with "normal" backbone, bases, and phosphodiester linkage). Percent degradation may be determined by using analytical HPLC to assess the loss of full length nucleic acids, or by any other suitable methods (e.g., by visualizing the products on a sequencing gel using staining, autoradiography, fluorescence, etc., or measuring a shift in optical density). Degradation is generally measured as a function of time. Comparison between unmodified and modified nucleic acids can be made by ratioing the percentage of intact modified nucleic acid to the percentage of intact unmodified nucleic acid. For example, if, after 15 minutes of exposure to a nuclease, 25% (i.e., 75% degraded) of an unmodified nucleic acid is intact, and 50% (i.e., 50% degraded) of a modified nucleic acid is intact, the modified nucleic acid is said to be 2 times (50% divided by 25%) more resistant to nuclease degradation than is the unmodified nucleic acid. Generally, a substantially nuclease resistant nucleic acid will be at least about 1.25 times more resistant to nuclease degradation than an unmodified nucleic acid with a corresponding sequence, typically at least about 1.5 times more resistant, preferably about 1.75 times more resistant, and more preferably at least about 10 times more resistant after 15 minutes of nuclease exposure. Percent acid degradation may be determined by using analytical HPLC or HPCE to assess the loss of full length nucleic acids, or by any other suitable methods (e.g., by visualizing the products on a sequencing gel using staining, autoradiography, fluorescence, etc., or measuring a shift in optical density). Degradation is generally measured as a function of time. Comparison between unmodified and modified nucleic acids can be made by ratioing the percentage of intact modified nucleic acid to the percentage of intact unmodified nucleic acid. For example, if, after 30 minutes of exposure to a low pH environment, 25% (i.e., 75% degraded) of an unmodified nucleic acid is intact, and 50% (i.e., 50% degraded) of a modified nucleic acid is intact, the modified nucleic acid is said to be 2 times (50% divided by 25%) more resistant to nuclease degradation than is the unmodified nucleic acid. Generally, substantially "acid resistant" nucleic acids will be at least about 1.25 times more resistant to acid degradation than an unmodified nucleic acid with a corresponding sequence, typically at least about 1.5 times more resistant, preferably about 1.75 more resistant, more preferably at least 5 times more resistant and even more preferably at least about 10 times more resistant after 30 minutes of exposure at 37°C to a pH of about 1.5 to about 4.5. Acidification of nucleic acids is the process by which protons (or positive hydrogen ions) are added to the reactive sites on a nucleic acid. As the number of reactive sites that are protonated increases, the pH is decreased, and the bacterial inhibiting activity of the nucleic acid is increased. Accordingly, the nucleic acids of the invention are protonated/acidified to give a pH when dissolved in water of less than pH 7 to about pH 1, or in preferred embodiments, pH 6 to about 1 or pH 5 to about 1. In other preferred embodiments, the dissolved nucleic acids have a pH from pH 4.5 to about 1 or, in a preferred embodiment, a pH of 4.0 to about 1, or, in a more preferred embodiment, a pH of 3.0 to about 1, or, in another more preferred embodiment, a pH of 2.0 to about 1. In a preferred embodiment, the end-blocked nucleic acids of the compositions are further acidified/protonated and methods of the invention are substantially nuclease resistant, substantially acid resistant, and preferably, both substantially nuclease resistant and substantially acid resistant. This embodiment includes nucleic acids completely or partially derivatized by one or more linkages from the group comprised of 2'-halogens, 2'-0-methyl, 2'-0-alkyl, 2'-0-alkyl-n(0-alkyl), 3 '-halogens, 3 -O-alkyl, 3'-0-alkyl-n(0-alkyl), phosphodiester linkages, phosphotriester linkages, phosphoramidate linkages, siloxane linkages, carbonate linkages, carboxymethylester linkages, acetamidate linkages, carbamate linkages, thioether linkages, bridged phosphoramidate linkages, bridged methylene phosphonate linkages, phosphorothioate linkages, methylphosphonate linkages, phosphorodithioate linkages, morpholino, bridged phosphorothioate linkages, sulfone internucleotide linkages, 3'-3' linkages, 5 -2' linkages, 5'-5' linkages, 2'-deoxy-erythropentofuranosyl, 2'-fluoro, 2'-0-alkyl nucleotides, 2'-0-alkyl-n(0-alkyl) phosphodiesters, morpholino linkages, p-ethoxy oligonucleotides, PNA linkages, p-isopropyl oligonucleotides, or phosphoramidates, sulfide linkages, sulfoxide linkages, sulfamate linkages, sulfamide linkages, formacetal/ ketal linkages, thioformacetal linkages, chiral phosphorous linkages, aminoalkylphosphorothioamidate linkages, and four residue group linkages., and any other backbone modifications. This embodiment also includes other modifications that render the nucleic acids substantially resistant to endogenous nuclease activity. Methods of rendering a nucleic acid nuclease resistant include, but are not limited to, covalently modifying the purine or pyrimidine bases that comprise the nucleic acid. For example, bases may be methylated, hydroxymethylated, or otherwise substituted (e.g., glycosylated) such that the nucleic acids comprising the modified bases are rendered substantially nuclease resistant. In a preferred embodiment, the nucleic acid will have a backbone substantially resistant to acid degradation, exonuclease digestion, and endonuclease digestion. In the most preferred embodiment an oligonucleotide is uniformly modified with 2'-0-alkyl, 2'-0-alkyl-n(0-alkyl), 3'-0- alkyl or 3'-0-alkyl-n(0-alkyl) groups, i.e., every base of the oligonucleotide is an O-alkyl or O-alkyl- n(O-alkyl) modified base. The end-blocked nucleic acids of the present invention preferably exhibit an enhanced ability to bind and enter target cells relative to previously disclosed nucleic acid preparations. The nucleic acids, and especially oligonucleotides, generally modulate physiological responses by acting as antisense or antigene inhibitors of cellular gene expression (when targeted to cellular nucleic acid sequences), or by acting aptamerically to alter the function of specific cellular proteins or polypeptides (when associating with target amino acid sequences contained in cellular peptides, polypeptides, and proteins). Alternatively, the nucleic acids of the invention, when targeted to an antibiotic resistant gene in bacteria, render the bacteria sensitive to a conventional antibiotic. In another embodiment, the nucleic acids of the current invention are used for diagnostic purposes. For example, nucleic acids of the current invention may be used as probes to detect complementary nucleic acids by contacting a nucleic acid of the invention with a nucleic acid sample under conditions that allow for the hybridization of the nucleic acid of the invention to any complementary nucleic acid present in the sample, and detecting such hybridization. Nucleic acids with a range of nuclease-resistant backbones were evaluated. As a result, a preferred embodiment of the present invention is an end-blocked nucleic acid with the chemical backbone structure of 5'-butanol-2'-0-alkyl RNA-butanol-3' or 2'-0-alkyl-0-alkyl. A particularly preferred embodiment of the present invention is a protonated/acidified nucleic acid with the chemical backbone structure of S'-butyl^'-O-methyl RNA-butanol-3', 5'-butyl-2'-0-alkyl-0-alkyl RNA- butanol-3' or 2'-0-alkyl-0-alkyl RNA that has a pH of 3 to 1 when dissolved in water. Nucleic Acid Synthesis Nucleic acids can be synthesized on commercially purchased DNA synthesizers from <luM to >lmM scales using standard phosphoramidite chemistry and methods that are well known in the art, such as, for example, those disclosed in Stec et al., J. Am. Chem. Soc. 106:6077-6089 (1984), Stec et al., J. Org. Chem. 50(20):3908-3913 (1985), Stec et al., J. Chromatog. 326:263-280 (1985), LaPlanche et al., Nuc. Acid. Res. 14(22):9081-9093 (1986), and Fasman, Practical Handbook of Biochemistry and Molecular Biology, 1989, CRC Press, Boca Raton, FL, herein incorporated by reference. Nucleic acids can be deprotected following phosphoramidite manufacturer's protocols. Unpurified oligonucleotides may be dried down under vacuum or precipitated and then dried. Sodium salts of oligonucleotides can be prepared using the commercially available DNA-Mate (Barkosigan Inc.) reagents or conventional techniques such as the commercially available exchange resin, e.g., Dowex, or by addition of sodium salts followed by precipitation, diafiltration, or gel filtration, etc. Nucleic acids to be purified can be chromatographed on commercially available reverse phase or ion exchange media, e.g., Waters Protein Pak, Pharmacia's Source Q, etc. Peak fractions can be combined and the samples desalted and concentrated by means of reverse phase chromatography on poly(styrene-divinylbenzene) based columns like Hamilton's PRP, or Polymer Labs PLRP. Alternatively, ethanol precipitation, diafiltration, or gel filtration may be used followed by lyophilization or solvent evaporation under vacuum in commercially available instrumentation such as Savant's Speed Vac. Optionally, small amounts of the nucleic acids may be electrophoretically purified using polyacrylamide gels. Lyophilized or dried-down preparations of nucleic acids can be dissolved in pyrogen-free, sterile, physiological saline (i.e., 0.85% saline), sterile Sigma water, and filtered through a 0.45 micron Gelman filter (or a sterile 0.2 micron pyrogen-free filter). The described nucleic acids may be partially or fully substituted with any of a broad variety of chemical groups or linkages including, but not limited to: phosphoramidates; phosphorothioates; alkyl phosphonates; 2'-0-methyls; 2'-modified RNAs; morpholino groups; phosphate esters; propyne groups; or chimerics of any combination of the above groups or other linkages (or analogues thereof). A variety of standard methods can be used to purify the presently described nucleic acids. In brief, the nucleic acids of the present invention can be purified by chromatography on commercially available reverse phase (for example, see the RAININ Instrument Co., Inc. instruction manual for the DYNAMAX®-300A, Pure-DNA reverse-phase columns, 1989, or current updates thereof, herein incorporated by reference) or ion exchange media such as Waters' Protein Pak or Pharmacia's Source Q (see generally, Warren and Vella, 1994, "Analysis and Purification of Synthetic Nucleic Acids by High-Performance Liquid Chromatography", in Methods in Molecular Biology, vol. 26; Protocols for Nucleic Acid Conjugates, S. Agrawal, Ed., Humana Press, Inc., Totowa, NJ; Aharon et al, 1993, J. Chrom. 698:293-301; and Millipore Technical Bulletin, 1992, Anttsense DNA: Synthesis, Purification, and Analysis). Peak fractions can be combined and the samples concentrated and desalted via alcohol (ethanol, butanol, isopropanol, and isomers and mixtures thereof, etc.) precipitation, reverse phase chromatography, diafiltration, or gel filtration. A nucleic acid is considered pure when it has been isolated so as to be substantially free of, inter alia, incomplete nucleic acid products produced during the synthesis of the desired nucleic acid. Preferably, a purified nucleic acid will also be substantially free of contaminants which may hinder or otherwise mask the antibacterial and/or antisense activity of the oligonucleotide. A purified nucleic acid, after acidification by one of the disclosed methods or by any other method known to those of skill in the art, is a protonated/acidified nucleic acid that has been isolated so as to be substantially free of, inter alia, excess protonating/acidifying agent. In general, where a nucleic acid is able to bind to, or gain entry into a target cell to modulate a physiological activity of interest, it shall be deemed as substantially free of contaminants that would render the nucleic acid less useful. In particular embodiments, the nucleic acids of the invention are composed of one or more of the following: partially or fully substituted phosphorothioates, phosphonates, phosphate esters, phosphoroamidates, 2'-modified RNAs, 3'-modified RNAs, peptide nucleic acids, propynes or analogues thereof. Acid and Nuclease Resistant Nucleic Acids Many nucleic acid backbones are not stable at low pH (e.g., pH 1-3) and experience depurination, although a number of backbones are relatively stable at pH 4-5. It has been discovered that 2'-0-alkyl, 3'-0-alkyl, and 2'-0-alkyl-n(0-alkyl) nucleic acids are stable at the desired pH of 2 to 1. In one embodiment, the invention includes nucleic acids that are substantially nuclease resistant. This includes nucleic acids completely derivatized by phosphorothioate linkages, 2'-0- methylphosphodiesters, 2'-0-alkyl, 2'-0-alkyl-n(0-alkyl), 2'-fluoro, 2'-deoxy-erythropentofuranosyl, p- ethoxy nucleic acids, p-isopropyl nucleic acids, phosphoramidates, chimeric linkages, and any other backbone modifications, as well as other modifications, which render the nucleic acids substantially resistant to endogenous nuclease activity. Additional methods of rendering nucleic acids nuclease resistant include, but are not limited to, covalently modifying the purine or pyrimidine bases that comprise the nucleic acid. For example, bases may be methylated, hydroxymethylated, or otherwise substituted (e.g., glycosylated) such that the nucleic acids comprising the modified bases are rendered substantially nuclease resistant. Although 2'-0-alkyl substituted nucleic acids exhibit marked acid stability and endonuclease resistance, they are sensitive to 3' exonucleases. In order to enhance the exonuclease resistance of 2'- O-alkyl substituted nucleic acids, the 3' and/or 5' ends of the ribonucleic acid sequence are preferably attached to an exonuclease blocking function. For example, one or more phosphorothioate nucleotides can be placed at either end of the oligoribonucleotide. Additionally, one or more inverted bases can be placed on either end of the oligoribonucleotide, or one or more alkyl, e.g., butanol-substituted nucleotides or chemical groups can be placed on one or more ends of the oligoribonucleotide. Accordingly, a preferred embodiment of the present invention is a protonated/acidified nucleic acid comprising a nucleic acid having the following structure: A-B-C wherein "B" is a 2'-0-alkyl or 2'-0-alkyl-n(0-alkyl) oligoribonucleotide between about 1 and about 98 bases in length, and "A" and "C" are respective 5' and 3' end blocking groups (e.g., one or more phosphorothioate nucleotides (but typically fewer than six), inverted base linkages, or alkyl, alkenyl, or alkynl groups or substituted nucleotides or 2'-0-alkyl-n(0-alkyl)). A partial list of blocking groups includes inverted bases, dideoxynucleotides, methylphosphates, alkyl groups, aryl groups, cordycepin, cytosine arabanoside, 2'-methoxy, ethoxy nucleotides, phosphoramidates, a peptide linkage, dinitrophenyl group, 2'- or 3'-0-methyl bases with phosphorothioate linkages, 3'-0-methyl bases, fluorescein, cholesterol, biotin, acridine, rhodamine, psoralen, glyceryl, methyl phosphonates, butyl, butanol, hexanol, and 3'-0-alkyls. An enzyme-resistant butanol blocking group preferably has the structure HO-CH 2 CH 2 CH 2 CH 2 (4-hydroxybutyl) which is also referred to as a C4 spacer. Even more preferably is a butyl blocking group, CH 3 CH 2 CH 2 CH 2 Another modified phosphodiester analogue that may be used in the nucleic acids of the invention is a p-ethoxy nucleic acid. The modifications of p-ethoxy nucleic acids are made in the phosphate backbone so that the modification will not interfere with the binding of these oligos to the target mRNA. p-Ethoxy oligos are made by adding an ethyl group to a nonbridging oxygen atom of the phosphate backbone. The chemical modifications of nucleic acids of the invention may also include one or more other known alterations in the chemical composition of the linkages of the polynucleotide that are known in the art to increase the stability and/or nuclease resistance of nucleic acids. These modifications may include, alone or in combination: phosphoramidate linkages, as described in U.S. Pats. No. 5,863,536, No. 5,837,835, No. 5,726,297, No. 5,684,143, No. 5,631,135, No. 5,599,922 and WO 99/10541; phosphorothioate linkages, as described in U.S. Pat. No. 5,652,355; sulfur linkages, e.g., sulfide, sulfoxide and sulfone linkage groups as described in U.S. Pat. No. 5,216,141; sulfamate or sulfamide linkages as described in U.S. Pat. No. 5,470,967; formacetal/ ketal linkages as disclosed in U.S. Pats. No. 5,264,562 and No. 5,264,564; thioformacetal linkages as described in U.S. Pat. No. 5,495,009; chiral phosphorous linkages, as described in U.S. Pat. No. 5,852,188; aminoalkylphosphorothioamidate linkages such as those described in U.S. Pats. No.5,563,253 and No. 5,536,821; terminal 3'-3' or 5'-5' intemucleotide linkages, as described in U.S. Pat. No. 5,750,669; and other intersugar 4 residue linkage groups as described in U.S. Pats. No. 5,610,289, No.5,602,240, No. 5,541,307, No. 5,386,023 and No. 5,378,825. Each of these patents is incorporated herein by reference to describe exemplary linkages that are optionally found in the acid stable end-blocked nucleic acids of the invention. The nucleic acids of the invention may be any combination of these modifications, such as chimeric phosphoramidate/phosphodiester molecules. Protonated/Acidifted Nucleic Acids Subsequent to, or during, the synthesis and purification steps, protonated/acidified forms of the described end-blocked nucleic acids can be generated by subjecting the purified, partially purified, or crude nucleic acids, to a low pH, or acidic, environment. Purified or crude nucleic acids can be protonated/acidified with acid, including but not limited to, phosphoric acid, nitric acid, hydrochloric acid, acetic acid, etc. For example, acid may be combined with nucleic acids in solution, or alternatively, the nucleic acids may be dissolved in an acidic solution. Excess acid may be removed by chromatography or in some cases by drying the nucleic acid. Other procedures to prepare protonated nucleic acids known to the skilled artisan are equally contemplated to be within the scope of the invention. Once the nucleic acids of the present invention have been protonated they may be separated from any undesired components like, for example, excess acid. The skilled artisan would know of many ways to separate the oligonucleotides from undesired components. For example, the oligonucleotide solution may be subjected to chromatography following protonation. In a preferred embodiment, the oligonucleotide solution is run over a poly(styrene- divinylbenzene) based resin column (e.g., Hamilton's PRP or Polymer Labs' PLRP) following protonation. The protonated/acidified nucleic acids can be used directly, or in a preferred embodiment, processed further to remove any excess acid and salt via precipitation, reverse phase chromatography, diafiltration, or gel filtration. The protonated/acidified oligos can be concentrated by precipitation, lyophilization, solvent evaporation, etc. When suspended in water or saline, the acidified nucleic acid preparations of the invention typically exhibit a pH between 1 and 4.5 depending upon 1) the level of protonation/acidification, which can be determined by how much acid is used in the acidification process, and 2) the concentration of the nucleic acid. Alternatively, nucleic acids can be protonated by passage over a cation exchange column charged with hydrogen ions. Uses of Oligonucleotides of the Present Invention Oligonucleotides of the present invention are useful for many applications. For example, these oligonucleotides are useful to modulate physiological processes. Oligonucleotides can participate in the formation of duplex and triplex complexes. Moreover, oligonucleotides are unique in that the formation of such duplex and triplex complexes is considerably more predictable than the formation of complexes between molecules of a different chemical nature like, for example, proteins, lipids, or sugars. The formation of a duplex or triplex structure between an oligonucleotide of the present invention and a target nucleic acid can interfere with functions of the target nucleic acid. Such target nucleic acids may be, for example, any RNA or DNA. Examples of RNAs and DNAs that can be targeted to modulate physiological processes are genomic DNA, mitochondrial DNA, viral DNA, bacterial DNA, mRNA, heterogeneous nuclear RNA ("hnRNA"), viral RNA, bacterial RNA. Or, for example, an oligonucleotide of the present invention may bind to a nucleic acid that a protein needs for its activity and thereby modulate the activity of the protein or the protein/nucleic acid complex. In addition to their ability to interact with nucleic acids, oligonucleotides of the present invention are also useful agents to modulate the activity of proteins. Such modulation may be accomplished, for example, by designing an oligonucleotide that can interact with the protein of interest, i.e., an oligonucleotide that acts as an aptamer. Screening protocols to identify oligonucleotides that can interact with a protein of interest are known to the skilled artisan. For example, one could generate a library that contains all possible or many different sequences of oligonucleotides of one or more than one length. Then, one could expose the library to the protein of interest to identify which oligonucleotides from the library the protein of interest will interact with. Such exposure may be carried out by, for example, having both in solution, i.e., the library of oligonucleotides and the protein of interest. By extracting the protein of interest from the solution with an antibody, one can isolate oligonucleotide species bound to the protein from those not bound. The sequence of bound oligonucleotides can easily be identified through routine experimentation. For example, one may attach stretches of a known sequence on each side of the oligonucleotides that are to be tested for their ability to bind to the protein of interest. Then, following the binding and extraction of the protein-nucleic acid complexes, one can amplify the oligonucleotides that can bind to the protein by using a variety of techniques known to the skilled artisan like, for example, the polymerase chain reaction. Other ways to identify oligonucleotides that can interact with a protein of interest can easily be devised. For example, one may bind either the protein of interest or the library of oligonucleotide species to a solid support like, for example, beads, filters or micro-arrays. Following exposure of the bound component, i.e., protein or oligonucleotides, to the unbound component, i.e., oligonucleotides or protein, one may identify the desired oligonucleotides in a variety of ways. For example, one may label the unbound component and thus screen for the desired bound component. For example, if oligonucleotides are bound to a filter and screened with a labeled protein, spots on the filter where labeled protein binds can be identified through exposure of the filter to a film. Such screening approaches can be modified according to many screening protocols known to the skilled artisan. In addition to their use for therapeutic purposes, oligonucleotides of the current invention are useful for other applications like, for example, cosmetic and diagnostic purposes. Cosmetic applications for oligonucleotides of the current invention include their topical application to enhance the visual appeal of skin. For example, oligonucleotides were shown useful to promote the tanning of skin. See Gilchrest et al., PCT Application No. WO 95/01773, which is incorporated herein by reference in its entirety. In addition, occurrences in the skin that in any way are or lead to noticeable but undesired signs or marks on the skin may be treated by using the oligonucleotides of the present invention. Or, for example, oligonucleotides of the current invention may be used for diagnostic purposes. Many diagnostic applications are known to the skilled artisan wherein an oligonucleotide is used to detect the presence of, for example, a nucleic acid of a bacterium or a vims in a sample. Oligonucleotides of the current invention can also be used as probe elements of a nucleotide microarray. Oligonucleotides of the current invention are also useful as anti-bacterial or anti-viral agents. For example, one may design an oligonucleotide that interacts with a nucleic acid or protein that is important for the propagation or survival of a bacteria or vims. The designed oligonucleotide can be used, for example, to treat an infection by bacteria or viruses that require the targeted nucleic acid or protein for their propagation or survival. Additionally, since the oligonucleotides of the invention demonstrate non-sequence-specific anti-bacterial effects, one may use non-targeted oligonucleotides as anti-bacterial agents. Selection of Targets for Oligonucleotides Oligonucleotides of the present invention can be targeted to a variety of molecules in living organisms and cells. For example, an mRNA molecule that encodes a protein could be targeted. If the protein causes a disease, the nucleic acid designed to target the mRNA for that protein would alleviate the symptoms of that disease by inhibiting the translation of the mRNA so that the level of the disease causing protein is downregulated. Most oligonucleotides are designed with complementarity to a region at or near the translational start site. However, other regions of an mRNA or an hnRNA may be targeted. For example, the 3' untranslated region of an mRNA may be targeted. In another example, an oligonucleotide may be complementary to a splice donor or acceptor site of an hnRNA. The skilled artisan would be able to determine which antisense sequences would be effective for a given target. Another example of using oligonucleotides of the present invention is the regulation of metabolic processes. For example, the activity of a particular protein factor like, for example, an enzyme, may be regulated by downregulating the translation of the appropriate mRNA. The processes in living organisms and cells that can be modulated this way are virtually without limit. The oligonucleotides of the current invention can be readily employed for any such modulation if an appropriate target is known. In Vivo Testing of Oligonucleotides When used in the therapeutic treatment of disease, an appropriate dosage of one or more oligonucleotides of the invention may be determined by any of several well established methodologies. For instance, animal studies are commonly used to determine the maximal tolerable dose, or MTD, of bioactive agent per kilogram weight. In general, at least one of the animal species tested is mammalian. Those skilled in the art regularly extrapolate doses for efficacy and avoiding toxicity to other species, including human. Additionally, therapeutic dosages may also be altered depending upon factors such as the severity of infection, and the size or species of the host. The LD 50 of the oligonucleotides of the invention has been shown to be more than 400 mg/Kg of body weight in mouse. The preferred dosage of the oligonucleotides of the invention is based upon the method of administration, as will be apparent to one skilled in the art upon reading this disclosure. Exemplary ranges of dosage for oral or topical administration are between 10 μg and 400 mg per day, and preferably between 1 mg and 200 mg per day. Where the therapeutic use of the presently described oligonucleotides is contemplated, the oligonucleotides are preferably administered in a pharmaceutically acceptable carrier, via oral, intranasal, rectal, topical, intraperitoneal, intramuscular, subcutaneous, intracranial, subdermal, transdermal, intratracheal methods, or the like. For example, topical diseases are preferably treated or prevented by formulations designed for topical application. Alternately, where the targeted disease state is in the gastrointestinal tract, preparations of oligonucleotides may be provided by oral dosing. Additionally, pulmonary sites of disease, e.g., asthma, may be treated both parenterally and by direct application of suitably formulated forms of the oligonucleotides to the lung by inhalation therapy. Where suitably formulated oligonucleotides are administered parenterally, the oligonucleotides can accumulate to relatively high levels in the kidneys, liver, spleen, lymph glands, adrenal gland, aorta, pancreas, bone marrow, heart, and salivary glands. Oligonucleotides also tend to accumulate to a lesser extent in skeletal muscle, bladder, stomach, esophagus, duodenum, fat, and trachea. Still lower concentrations are typically found in the cerebral cortex, brain stem, cerebellum, spinal cord, cartilage, skin, thyroid, and prostate (see generally Crooke, 1993, Antisense Research and Applications, CRC Press, Boca Raton, FL). One of ordinary skill will appreciate that, from a medical practitioner's or patient's perspective, virtually any alleviation or prevention of an undesirable symptom would be desirable. Thus, the terms "treatment", "therapeutic use", or "medicinal use" used herein shall refer to any and all uses of the claimed oligonucleotides that remedy a disease state or symptoms, or otherwise prevent, hinder, retard, or reverse the progression of disease or other undesirable symptoms in any way whatsoever. Preferably, animal hosts may be treated using the oligonucleotides of the present invention with sequences appropriate for the particular animal. Targeted species include, but are not limited to, invertebrates, vertebrates, birds, mammals such as pigs, goats, sheep, cows, dogs, cats, and particularly humans. Pharmaceutical Compositions and Delivery Where in vivo use is contemplated, the oligonucleotides of the present invention may be formulated with a variety of physiological carrier molecules. For example, the oligonucleotides may be combined with a lipid, cationic lipid, or anionic lipid (which may be preferred for protonated/acidified oligonucleotides) and the resulting oligonucleotide/lipid emulsion, or liposomal suspension may, inter alia, effectively increase the in vivo half-life of the oligonucleotide. Protonation/acidification of oligonucleotides of the present invention facilitates their encapsulation in anionic lipids which are thought to have a number of advantages over cationic liposomes (R.J. Lee and L. Huang, "Lipidic Vector Systems for Gene Transfer", in Critical Reviews in Therapeutic Drug Carrier Systems, 14(2):173-206 (1997)). Specifically, anionic liposomes are likely to be less toxic than cationic liposomes, they exhibit lower non-specific uptake, and they can be targeted with the appropriate ligands to specific cells. Examples of suitable anionic lipids for use with protonated/acidified oligonucleotides include, but are not limited to, cardiolipin, dimyristoyl, dipalmitoyl, or dioleoyl phosphatidyl choline or phosphatidyl glycerol, pahnitoyloleoyl phosphatidyl choline or phosphatidyl glycerol, phosphatidic acid, lysophosphatidic acid, phosphatidyl serine, phosphatidyl inositol, and anionic forms of cholesterol. The use of cationic, anionic, and/or neutral lipid compositions or liposomes is generally described in International Publications Nos. WO 90/14074, WO 91/16024, WO 91/17424, and U.S. Pat. No. 4,897,355, herein incoφorated by reference. By assembling nucleic acids into lipid-associated stmctures, the nucleic acids may be targeted to specific cell types by the incorporation of suitable targeting agents (i.e., specific antibodies or receptors) into the nucleic acid/lipid complex. Pharmaceutical compositions containing the nucleic acids of the invention in intimate admixture with a pharmaceutical carrier can be prepared according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., intravenous, oral, topical, aerosol (for topical or inhalation therapy), suppository, parenteral, or spinal injection. In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations (such as, for example, suspension, elixirs, and solutions); or carriers such as starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations (such as, for example, powders, capsules and tablets). Because of their ease in admimstration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar-coated or enteric-coated by standard techniques. For parenteral application by injection, preparations may comprise an aqueous solution of a water soluble, or solubilized, and pharmaceutically acceptable form of the nucleic acid in an appropriate saline solution. Injectable suspensions may also be prepared using appropriate liquid carriers, suspending agents, agents for adjusting the isotonicity, preserving agents, and the like. Actual methods for preparing parenterally administrable compositions and adjustments necessary for administration to subjects will be known or apparent to those skilled in the art and are described in more detail in, for example, Remington's Pharmaceutical Science, 15th Ed., Mack Publishing Company, Easton, PA (1980), which is incoφorated herein by reference. The presently described nucleic acids should be parenterally administered at concentrations below the maximal tolerable dose (MTD) established for the nucleic acids. For topical administration, the carrier may take a wide variety of forms depending on the preparation, which may be a cream, dressing, gel, lotion, ointment, or liquid. An exemplary carrier for a topical carrier is methyl cellulose. Aerosols are prepared by dissolving or suspending the nucleic acid in a propellant such as ethyl alcohol or in propellant and solvent phases. The pharmaceutical compositions for topical or aerosol form will generally contain from about 0.01% by weight (of the nucleic acid) to about 40% by weight, preferably about 0.02% to about 10% by weight, and more preferably about 0.05% to about 5 % by weight depending on the particular form employed. Suppositories are prepared by mixing the nucleic acid with a lipid vehicle such as theobroma oil, cacao butter, glycerin, gelatin, or polyoxyethylene glycols. The presently described acid stable, end-blocked nucleic acids may be administered to the body by virtually any means used to administer conventional therapeutics. A variety of delivery systems are well known in the art for delivering bioactive compounds to an animal. These systems include, but are not limited to, intravenous or intra-muscular or intratracheal injection, nasal spray, aerosols for inhalation, and oral or suppository administration. The specific delivery system used depends on the location of the disease, and it is well within the skill of one in the art to determine the location of the disease and to select an appropriate delivery system. Cosmetic Use of Antibacterial Nucleic Acids The protonated/acidified nucleic acids of the invention may be used in cosmetic products such as lotions, creams, or topical solutions. The nucleic acids of the invention may be used both as an antibacterial agent, such as in a lotion, and as a preservative to prevent and/or retard growth of bacteria in the cosmetic preparation. Thus, the nucleic acids may be used with any known cosmetic preparation, provided the composition of the preparation is sufficiently low in pH to retain the activity of the protonated nucleic acid, i.e., 7.0 or below, and provided that the nucleic acids are present in an amount sufficient to have an antibacterial effect, preferably between 0.25 wt % and 10.0 wt %, more preferably between 0.5 wt % and 5.0 wt%. The cosmetic composition of the invention may contain any of a number of additives that are themselves active ingredients, such as a glycolic or alpha-hydroxy acids, vitamin A palmitate (retinyl palmitate) and/or vitamin E acetate (tocopheryl acetate). Each of these is preferably present in an amount from about 0.5 wt. % to about 5 wt %. In addition, a UV absorbing or blocking material, such as PABA, may be used. Other compounds may also be added to have additional moisturizing effects and to improve the consistency of the composition. Examples of such compounds include, but are not limited to: certyl esters wax, stearyl alcohol, cetyl alcohol, glycerin, methyl paraben, propyl paraben, quatemium-15, humectants, volatile methylsiloxane fluids, and polydiorganosiloxane-polyoxyalkylene. See, e.g., U.S. Pat Nos. 5,153,230 and 4,421,769, which are both incoφorated herein by reference. If it is desirable for the composition to have additional cleaning effects, chemicals such as sodium lauryl sulfate or a metal salt of a carboxylic acid may be added. The nucleic acids of the invention may be especially useful in topical anti-acne compositions, since they have good efficacy against a broad spectrum of bacteria, they have low skin irritation, and they are chemically stable. Such compositions are preferably aqueous, as oil-based compositions may exacerbate the acne condition. A wide variety of nonvolatile emollients are useful herein, nonlimiting examples of which are listed ϊnMcCutcheon 's, Vol. 2 Functional Materials, North American Edition, (1992), pp. 137-168, which is incoφorated herein by reference in its entirety, and CTFA Cosmetic Ingredient Handbook, Second Edition (1992) which lists Skin-Conditioning Agents at pp. 572-575 and Skin Protectants at p. 580, which is also incoφorated herein by reference in its entirety. Among the nonvolatile emollient materials useful herein especially preferred are silicones, hydrocarbons, esters and mixtures thereof. Examples of silicone emollients include polyalkylsiloxanes, cyclic polyalkylsiloxanes, and polyalkylarylsiloxanes. The polyalkylsiloxanes useful herein include, for example, polyalkylsiloxanes with viscosities of from about 0.5 to about 100,000 centistokes at 25°C. Such polyalkylsiloxanes correspond to the general chemical formula R 3 SiO[R 2 SiO] ϊ SiR 3 wherein R is an alkyl group (preferably R is methyl or ethyl, more preferably methyl) and : is an integer from 0 to about 500, chosen to achieve the desired molecular weight. Commercially available polyalkylsiloxanes include the polydimethylsiloxanes, which are also known as dimethicones, nonlimiting examples of which include the Vicasil® series sold by General Electric Company and the Dow Corning® 200 series sold by Dow Corning Coφoration. Specific examples of polydimethylsiloxanes useful as emollients herein include Dow Corning® 200 fluid having a viscosity of 0.65 centistokes and a boiling point of 100°C, Dow Corning® 225 fluid having a viscosity of 10 centistokes and a boiling point greater than 200°C, and Dow Corning® 200 fluids having viscosities of 50, 350, and 12,500 centistokes, respectively, and boiling points greater than 200°C. Cyclic polyalkylsiloxanes useful herein include those corresponding to the general chemical formula [SiR 2 0]„ wherein R is an alkyl group (preferably R is methyl or ethyl, more preferably methyl) and n is an integer from about 3 to about 8, more preferably n is an integer from about 3 to about 7, and most preferably n is an integer from about 4 to about 6. When R is methyl, these materials are typically referred to as cyclomethicones. Commercially available cyclomethicones include Dow Corning® 244 fluid having a viscosity of 2.5 centistokes and a boiling point of 172°C, which primarily contains the cyclomethicone tetramer (i.e., «=4), Dow Corning® 344 fluid having a viscosity of 2.5 centistokes and a boiling point of 178°C, which primarily contains the cyclomethicone pentamer (i.e., n=5), Dow Corning® 245 fluid having a viscosity of 4.2 centistokes and a boiling point of 205°C, which primarily contains a mixture of the cyclomethicone tetramer and pentamer (i.e., n-4 and 5), and Dow Corning® 345 fluid having a viscosity of 4.5 centistokes and a boiling point of 217°C, which primarily contains a mixture of the cyclomethicone tetramer, pentamer, and hexamer (i.e., n=4, 5, and 6). Also useful are materials such as trimethylsiloxysilicate, which is a polymeric material corresponding to the general chemical formula [(CH 2 ) 3 SiO, ] x [Si0 2 ]y, wherein x is an integer from about 1 to about 500 and y is an integer from about 1 to about 500. A commercially available trimethylsiloxysilicate is sold as a mixture with dimethicone as Dow Corning® 593 fluid. Also useful herein are dimethiconols, which are hydroxy terminated dimethyl silicones. These materials can be represented by the general chemical formulas R 3 SiO[R 2 SiO] x SiR 2 OH and HOR 2 SiO[R 2 SiO] x SiR 2 OH wherein R is an alkyl group (preferably R is methyl or ethyl, more preferably methyl) and x is an integer from 0 to about 500, chosen to achieve the desired molecular weight. Commercially available dimethiconols are typically sold as mixtures with dimethicone or cyclomethicone (e.g., Dow Corning® 1401, 1402, and 1403 fluids). Also useful herein are polyalkylaryl siloxanes, with polymethylphenyl siloxanes having viscosities from about 15 to about 65 centistokes at 25°C being preferred. These materials are available, for example, as SF 1075 methylphenyl fluid (sold by General Electric Company) and 556 Cosmetic Grade phenyl trimethicone fluid (sold by Dow Corning Coφoration). Hydrocarbons useful herein include straight and branched chain hydrocarbons having from about 10 to about 30 carbon atoms, more preferably from about 12 to about 24 carbon atoms, and most preferably from about 16 to about 22 carbon atoms. Nonlimiting examples of these hydrocarbon materials include dodecane, squalane, cholesterol, 5 hydrogenated polyisobutylene, docosane (i.e., a C 22 hydrocarbon), hexadecane, isohexadecane (a commercially available hydrocarbon sold as Permethyl® 101A by Presperse, South Plainsfield, NJ). Other hydrocarbon materials useful herein include paraffins and mineral oils such as USP light mineral oil and or USP heavy mineral oil (e.g., Klearol® available from Witco Coφ., Melrose Park, IL). Also useful as nonvolatile emollients are esters, including esters of monofunctional and difunctional fatty acids that have been esterified with alcohols and polyols (i.e., alcohols having two or more hydroxy groups). A wide variety of esters are useful herein, with long chain esters of long chain fatty acids being preferred (i.e., C10-40 fatty acids esterified with C10-40 fatty alcohols). Nonlimiting examples of esters useful herein include those selected from the group consisting of diisopropyl adipate, isopropyl myristate, isopropyl palmitate, myristyl propionate, ethylene glycol distearate, 2- ethylhexyl palmitate, isodecyl neopentanoate C 12 . 15 alcohols benzόate, di-2-ethylhexyl maleate, cetyl palmitate, myristyl myristate, stearyl stearate, cetyl stearate, behenyl behenrate, and mixtures thereof. Use of Antibacterial Nucleic Acids in Disinfectants The nucleic acids of the invention may also find use as disinfectants, and particularly as liquid disinfectant preparations having biostatic or preferably biocidal properties. The disinfectant solution contains at least a sufficient amount of nucleic acid of the invention, and may also contain other active ingredients with biostatic and/or biocidal properties. For example, the disinfectant may contain nucleic acids of the invention with a suitable concentration of a quaternary ammonium compound such as: dimethylbenzyldodecylammonium chloride, dimethylbenzyl decylammonium chloride, dimethylbenzyl decylammonium bromide, dimethylbenzylloctylammonium chloride, and cocosalkyldimethylbenzylammonium chloride. In another example, suitable microbicidal biguanidine compounds, such as oligohexamethylene biguanide salts and bisbiguanides, can be used. See, e.g., U.S. Pat. No. 5,030,659 which is incoφorated herein by reference. Additional biocidal ingredients include aldehydes, phenol derivatives, and halogen phenyl derivatives. See, e.g., U.S. Pat. No. 5,767,054, which is incoφorated herein by reference. Other compounds with such activity, as will be recognized by those skilled in the art, may also be used in conjunction with the nucleic acid of the invention. In addition to the described active components, the disinfectant preparations of the invention may contain other typical components depending on the desired use of the formulation. In particular, an acidifier may be used to keep the pH range of the disinfection solution below 7. Suitable solvents for the nucleic acids and/or the other active ingredients may be employed, and preferably are water or water miscible organic solvents. Solutions such as these may be readily sprayed using compressed air or any other propellants known by those in the art. These preparations of the invention are especially suitable for surface disinfection in medically-related environments, such as hospitals, veterinary clinics, dental and medical offices and the like. Use of solutions of the invention in the sterilization of surgical instruments is especially preferred. These preparations are also useful in public areas such as schools, public transport, restaurants, hotels, and laundries. The disinfectants also find use in home as sanitizers for toilets, basins, and kitchen areas. The protonated/acidified nucleic acids of the invention may also be used in disinfection solutions for skin. Such compositions contain the nucleic acid of the invention in a solution that is in a vehicle suitable for topical use. The disinfectant may be of the quick-drying variety, in which case it is desirable for the nucleic acid to be in an ethanol base. Such solutions preferably contain an emollient for the skin as well, since the alcohol tends to be extremely drying to skin. Examples of suitable emollients include, but are not limited to: a polyhydric alcohol such as polyethylene glycol, glycerin, diglycerin, propylene glycol, butylene glycol, erythritol, dipropylene glycol, and sorbitol. The amount of emollient may be in the range of 0.1-3.0 w/w%, and more preferably in the range 0.2-1.5 w/w%. In the case where the content of the emollient is less than 0.1 wt% it may not be very effective, and over 3.0% the solution may be overly sticky. Disinfectant solutions for the skin are especially useful in disinfection of hands following medical treatment or waste management. Disinfection may also be useful in surgical settings, both for the medical staff and to sterilize the area of surgery on the patient. EXAMPLES The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the present invention, and are not intended to limit the scope of what the inventors regard as their invention nor are they intended to represent that the experiments below are all or the only experiments performed. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperature, etc.) but some experimental errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Centigrade, and pressure is at or near atmospheric. EXAMPLE 1 : Synthesis, Purification and Protonation/Acidification of Nucleic Acids Nucleic acids were synthesized using commercial phosphoramidites on commercially purchased DNA synthesizers from <1 uM to >lmM scales using standard phosphoramidite chemistry and methods that are well known in the art, such as, for example, those disclosed in Stec et al. , J. Am. Chem. Soc. 106:6077-6089 (1984), Stec et al., J. Org. Chem. 50(20):3908-3913 (1985), Stec et α/., J. Chromatog. 326:263-280 (1985), LaPlanche et al. , Nuc. Acid. Res. 14(22):9081-9093 (1986), and Fasman, Practical Handbook of Biochemistry and Molecular Biology, 1989, CRC Press, Boca Raton, FL, herein incoφorated by reference. Nucleic acids were deprotected following phosphoramidite manufacturer's protocols. Unpurified nucleic acids were either dried down under vacuum or precipitated and then dried. Sodium salts of nucleic acids were prepared using the commercially available DNA-Mate (Barkosigan Inc.) reagents or conventional techniques such as commercially available exchange resin, e.g., Dowex, or by addition of sodium salts followed by precipitation, diafiltration, or gel filtration, etc. A variety of standard methods were used to purify/produce the presently described nucleic acids. In brief, nucleic acids were purified by chromatography on commercially available reverse phase (for example, see the RAININ Instrument Co., Inc. instmction manual for the DYNAMAX®- 300A, Pure-DNA reverse-phase columns, 1989, or current updates thereof, herein incoφorated by reference) or ion exchange media such as Waters' Protein Pak or Pharmacia's Source Q (see generally Warren and Vella, 1994, "Analysis and Purification of Synthetic Nucleic Acids by High-Performance Liquid Chromatography", in Methods in Molecular Biology, vol. 26; Protocols for Nucleic Acid Conjugates, S. Agrawal, Ed. Humana Press, Inc., Totowa, NJ; Aharon et al., 1993, J. Chrom. 698:293-301; and Millipore Technical Bulletin, 1992, Antisense DNA: Synthesis, Purification, and Analysis). Peak fractions were combined and the samples were concentrated and desalted via alcohol (ethanol, butanol, isopropanol, and isomers and mixtures thereof, etc.) precipitation, reverse phase chromatography, diafiltration, or gel filtration or size-exclusion chromatography, or a combination of any or all of these concentration/desalting techniques .. Subsequently, or during the above steps, protonated/acidified forms of the described nucleic acids can be generated by subjecting the purified, or partially purified, or crude nucleic acids, to a low pH, or acidic, environment. Purified or cmde nucleic acids were protonated/acidified with acid, including but not limited to, phosphoric acid, nitric acid, hydrochloric acid, acetic acid, etc. Pooled fractions of a SAX-purified nucleic acid (at approximately 2-25 A 260 per ml) were pumped onto a poly(styrene-divinylbenzene) based column, such as Polymer Labs' PLRP or Hamilton's PRP-1 or PRP-3. This was followed immediately with an excess of dilute acid (e.g., lOOmM HC1) until the eluent was acidic. The column was then washed with purified water (no salt or buffers) until the conductivity of the eluent returned to essentially background levels and background pH. The nucleic acids were then eluted with a suitable aqueous organic solution and then dried down in a commercially available vacuum evaporator. Alternatively, the nucleic acids were suspended in dilute acid and either chromatographed over the PRP or similar poly(styrene-divinylbenzene) based columns as described above, or chromatographed over a size exclusion column or gel filtration column (e.g., BioRad P2 or P4) using water as solvent. Alternatively, a desalted nucleic acid may be dissolved in alkaline salt solution (e.g., 0.4 M NaCl and pH 12, 25 mM NaOH), run on a PRP or similar poly(styrene-divinylbenzene) based column, washed with acid followed by water, and then eluted, as described above. Alternatively, a nucleic acid may be chromatographed over a cation exchange column that is in the FT form, collected and dried down as described above. Nucleic acids were also acidified by adding an acid, e.g., HCl (0.1 N), directly to a nucleic acid solution (approximately 300 A 260 per ml) until the pH of the solution reached pH 1 to pH 3. The acidified nucleic acids can then be run over an acid stable size exclusion column such as a BioRad P- gel column. Lyophilized or dried-down preparations of nucleic acids to be used in bacterial experiments were dissolved in pyrogen-free, sterile, physiological saline (i.e., 0.85% saline), sterile Sigma water, and filtered through a 0.45 micron Gelman filter (or a sterile 0.2 micron pyrogen-free filter prior to animal studies). When suspended in water or saline, the nucleic acid preparations typically exhibited a pH between 1 and 4.5 depending upon the level of protonation/acidification, which is determined by how much acid is used in the acidification process . EXAMPLE 2: Acid Stability of the Oligonucleotides of the Invention Homopolymers of 2'-0-methyl A, C, G, and U twelve bases long, were synthesized with 3' and 5' inverted T-blocked ends. They were purified, desalted, lyophilized, and dissolved at 300 A 260 per ml in sterile water. Samples were removed and diluted 1 to 4 with either 0.1 N HCl or 1.0 N HCl to give final pHs of approximately 1 and 0, respectively, and placed in a heat block at 39 °C. Aliquots were taken at 0, 2, 4 and 24 hours, diluted 1:20 into a solution of 0.025 M NaOH and 0.03 M NaCl, stored at -20 °C until being run on an analytical HPLC under strongly denaturing conditions on an anion exchange column. % Full Length Homopolvmer pH Ohr 2 hr 4 hr 24 hr A 1 99 99 99 99 C 1 99 99 99 96 G 1 96 98 98 98 U 1 97 97 97 A 0 99 99 99 99 C 0 99 99 98 97 G 0 96 97 97 89 U 0 97 97 96 It was evident that there is essentially no degradation at pH 1 and 39 ° C and only slight degradation over 24 hours at pH 0 and 39°C. EXAMPLE 3 : Acid Stability of the Oligonucleotides of the Invention A 14 mer heteropolymer (SEQ ID NO: 1) was synthesized as a regular phosphodiester DNA (0), a phosphorothioate DNA (S), an unblocked 2'-0-methyl RNA (2'om), a 2'-0-methyl RNA with 3' and 5' butanol blocked ends (B2'om), and a phosphorothioate chimera having four 2'-0-methyl phosphorothioate bases on either side of 6 interior phosphorothioate DNA bases (SD). They were purified, desalted, lyophilized, and dissolved at 300 A 260 per ml in sterile water. Samples were removed and diluted 1 to 4 with 0.1 N HCl to give a final pH of approximately 1.5, and placed in a heat block at 39 C C. Aliquots were taken at the times indicated and diluted 1:20 into a solution of 0.025 M NaOH and 0.03 M NaCl, and were run on an analytical HPLC under strongly denaturing conditions on an anion exchange column. Initially all but the end-blocked 2'-0-methyl RNA solutions became cloudy upon addition of the HCl. Upon heating, both the phosphodiester DNA and the unblocked 2'-0-methyl RNA became clear. The two oligonucleotides with phosphorothioate linkages appeared cloudy until about 2 hours when they slowly began to clear as they decomposed. % Ful 1 Length Oligo O hr 0.5 hr 1.0 hr 2 hr 4 hr 6 hr I d 2 d 3 d 5 d 10 d 20 d O 99 38 10 0 0 0 0 - - - - - S 95 65 29 1 0 0 0 - - - - - SD 97 83 70 49 0 0 0 - - - - - 2'om 99 99 99 99 98 98 98 96 94 94 87 80 B2'om 100 100 100 100 99 99 98 97 97 95 90 81 The 2 -O-methyl oligonucleotides, both unblocked and blocked, are far more stable than the corresponding phosphodiester, phosphorothioate, or a mixed 2'-0-methyl phosphorothioate structure that Agrawal et al. recommended to increase bioavailability. EXAMPLE 4: Human Semm Stability Study With and Without 3' and 5' End-blocks A 14 mer heteropolymer (SEQ ID NO:l) was synthesized as a regular phosphodiester DNA, a phosphorothioate DNA, an unblocked 2'-0-methyl RNA, and a 2'-0-methyl RNA with 3' and 5' butanol blocked ends. They were purified, desalted, lyophilized, and dissolved at 300 A 260 per ml in sterile water. Samples were removed, diluted into human serum (Sigma, H 2520), and incubated at 37 °C. Aliquots were taken at 2 and 4 days and diluted and filtered before being mn on an analytical HPLC under strongly denaturing conditions on an anion exchange column. % of Full Length Oliffn Polymer t = 0 2d 4d Phosphodiester-DNA 100 65 35 Unblocked 2'-0-methyl RNA 100 87 72 End-Blocked 2'-0-methyl RNA 100 100 100 Phosphorothioate 100 100 100 EXAMPLE 5: Acid Stability of the Oligonucleotides of the Invention A 14 mer heteropolymer (SEQ ID NO:l) was synthesized as a 3'-0-methyl phosphodiester (ASM-3') and a 2'-0-propargyl (-CH2-C≡CH) (ASM P). A 12 mer homopolymer of 2'- methoxyethoxy A was also made (MEA). They were purified, desalted, lyophilized, and dissolved at 300 A 260 per ml in sterile water. Samples were removed and diluted 1 to 4 with 0.1 N HCl to give a final pH of approximately 1.5, and placed in a heat block at 39 ° C . Aliquots were taken at the times indicated and diluted 1:20 into 0.025 M NaOH, 0.03 M NaCl. The samples were n on an analytical HPLC under strongly denaturing conditions on an anion exchange column. % Full Length Polymer 0 hr 0.5 hr 1.0 hr 2 hr 4 hr 8 hr I d MEA 98 98 98 98 98 99 98 ASM-3' 97 96 96 96 93 95 92 ASM-P 96 94* 69* 0 0 0 0 *Note: Most of the absorbance vanished from the ASM-P within 30 minutes, i.e., over 90% had vanished. A similar study using a methyl phosphonate backbone indicated it was stable for at least 2 hours but was noticeably degraded by 24 hours. EXAMPLE 6: Acid Stability of the Oligonucleotides of the Invention Versus Phosphodiester Oligonucleotides A 14 mer heteropolymer (SEQ ID NO: 1) was synthesized as a phosphodiester (DNA version) and as a 2'-0-methyl phosphodiester (2'-0-methyl). Each nucleotide in a single oligonucleotide shared the same backbone chemistry, i.e., all nucleotides in the 2'-0-methyl oligonucleotide had a 2'-0-methyl group on the sugar moiety. They were purified, desalted, lyophilized, and dissolved at 300 A 260 per ml in sterile water. Samples were removed and diluted 1 to 4 with 0.1 N HCl to give a final pH of approximately 1.5, and placed in a heat block at 39 °C. Aliquots were taken at the times indicated and diluted 1:20 into 0.025 M NaOH, 0.03 M NaCl. The samples were run on an analytical HPLC under strongly denaturing conditions on an anion exchange column. The results of oligonucleotide degradation are as follows, with percentage representing the oligonucleotides still present after exposure to acid: Sequence - cgt gtc agg aga ac % Full length Time 0 2 hr 1 day 5 days DNA Version 99 0 0 0 2'-0-methyl 99 99 99 95 Thus, the addition of a 2'-0-R group, here a 2'-0-methyl group, to the 2' residue of the sugar group significantly increased the stability of the molecule (See Figure 1). EXAMPLE 7: Acid Stability of Homopolymer Oligonucleotides of the Invention Versus Phosphodiester Oligonucleotides Next, the effect of the sequence of the altered oligonucleotide was examined for its potential effect on acid stability. Three 14 mer adenine homopolymers (SEQ ID NO:2) were synthesized as a phosphodiester (DNA version) and as a 2'-0-methyl phosphodiester (2'-0-methyl), and as 2'-methoxy ethoxy phosphodiesters. Each nucleotide in a single oligonucleotide shared the same backbone chemistry, i.e., all nucleotides in the 2'-0-methyl oligonucleotide had a 2'-0-methyl group on the sugar moiety. These oligonucleotides were purified, desalted, lyophilized, and dissolved at 300 A 260 per ml in sterile water. Samples were removed and diluted 1 to 4 with 0.1 N HCl to give a final pH of approximately 1.5, and placed in a heat block at 39°C. Aliquots were taken at the times indicated and diluted 1:20 into 0.025 M NaOH, 0.03 M NaCl. The samples were run on an analytical HPLC under strongly denaturing conditions on an anion exchange column. The results of oligonucleotide degradation are as follows, with percentage representing the oligonucleotides still present after exposure to acid: Sequence - aaa aaa aaa aaa % Full length Time 0 1 day DNA version 98 38 2'-0-methyl 99 99 2'-methoxy ethoxy 98 98 Thus, the addition of a 2'-0-R group (e.g., 2'-0-methyl group) or a 2'-0-R-0-R group (e.g., a methoxy ethoxy group) to the 2' residue of the sugar group significantly increased the stability of the molecule (See Figure 2). EXAMPLE 8: Acid Stability of the Oligonucleotides of the Invention Versus Phosphodiester Oligonucleotides A 14 mer heteropolymer (SEQ ID NO: 1) is synthesized as a phosphodiester (DNA version) and as a 2'-fluorine phosphodiester (2'-F). Each nucleotide in a single oligonucleotide shares the same backbone chemistry, i.e., all nucleotides in the 2'-F oligonucleotide have a 2'-F on the sugar moiety. The oligonucleotides are purified, desalted, lyophilized, and dissolved at 300 A 260 per ml in sterile water. Samples are removed and diluted 1 to 4 with 0.1 N HCl to give a final pH of approximately 1.5, and placed in a heat block at 39°C. Aliquots are taken at the times indicated and diluted 1:20 into 0.025 M NaOH, 0.03 M NaCl. The samples are mn on an analytical HPLC under strongly denaturing conditions on an anion exchange column. The results of oligonucleotide degradation are as follows, with percentage representing the oligonucleotides still present after exposure to acid: Sequence - cgt gtc agg aga ac % Full length Time 0 2 hr 1 day 5 days DNA Version 99 0 0 0 2'-F 99 99 99 94 Thus, the addition of a 2'-R group, here a 2'-F, to the 2' residue of the sugar group significantly increased the stability of the molecule (see Figure 3). EXAMPLE 9: Acid Stability of the Oligonucleotides of the Invention Versus Sulfur DNA Molecules A 14 mer heteropolymer was synthesized as a Sulfur DNA version and as a 2'-0-methyl Sulfur RNA. Both stmctures are shown in Figure 4. Each nucleotide in a single oligonucleotide shared the same backbone chemistry, i.e., all nucleotides in the 2'-0-methyl oligonucleotide have a 2'- O-methyl group on the sugar moiety. A 14 mer heteropolymer was synthesized, purified, desalted, lyophilized, and dissolved at 300 A 260 per ml in sterile water. Samples were removed and diluted 1 to 4 with 0.1 N HCl to give a final pH of approximately 1.5, and placed in a heat block at 39 °C. Aliquots were taken at the times indicated and diluted 1 :20 into 0.025 M NaOH, 0.03 M NaCl. The samples were run on an analytical HPLC under strongly denaturing conditions on an anion exchange column. The results of oligonucleotide degradation are as follows, with percentage representing the oligonucleotides still present after exposure to acid: Sequence - cgt gtc agg aga ac % Full length Time 0 2 hr 1 day 6 days Sulfur DNA version 96 1 0 0 Sulfur 2'-0-methyl 99 99 99 98 Thus, the addition of a 2'-0-R group (e.g., 2'-0-methyl group) or a 2'-0-R-0-R group (e.g., a methoxy ethoxy group) to the 2' residue of the sugar group significantly increased the stability of a sulfur DNA molecule (see Figure 4). EXAMPLE 10: Acid Stability of Phosphoramidate Oligonucleotides of the Invention A 14 mer phosphoramidate linked heteropolymer (SEQ ID NO: 1) is synthesized with either a proton, a 2'-0-methyl, or a 2'-0-methoxyethoxy on each nucleotide. Each nucleotide in a single oligonucleotide shared the same backbone chemistry, i.e. all nucleotides in the 2'-0-methyl oligonucleotide have a 2'-0-methyl group on the sugar moiety, and all nucleotides in the 2'-0- methoxyethoxy oligonucleotide have a 2'-0-methoxyethoxy on the sugar moeity. A 14 mer heteropolymer is synthesized, purified, desalted, lyophilized, and dissolved at 300 A 260 per ml in sterile water. Samples are removed and diluted 1 to 4 with 0.1 N HCl to give a final pH of approximately 1.5, and placed in a heat block at 39 °C. Aliquots are taken at the times indicated and diluted 1:20 into 0.025 M NaOH, 0.03 M NaCl. The samples are run on an analytical HPLC under strongly denaturing conditions on an anion exchange column. The results of oligonucleotide degradation are as follows, with percentage representing the oligonucleotides still present after exposure to acid: Sequence - cgt gtc agg aga ac % Full length Time 0 2 hr 1 day 6 days Phosphoramidate DNA version 96 1 0 0 Phosphoramidate 2'-0-methyl 99 99 99 98 Thus, the addition of a 2'-0-R group (e.g., 2'-0-methyl group) or a 2'-0-R-0-R group (e.g., a methoxyethoxy group) to the 2' residue of the sugar group significantly increased the stability of a phosphoramidate DNA molecule (see Figure 5). EXAMPLE 11: Acid Stability of the Oligonucleotides of the Invention Versus Phosphodiester Oligonucleotides Oligonucleotides were synthesized having a combination of altered and non-altered nucleotides. A 14 mer heteropolymer with sequence CGTGTCAGGAGAAC (SEQ ID NO: 1) was synthesized in three forms: one with deoxyribose guanines (DNA Gs), one with 2'-0-methyl guanines, and one with 2'-methoxy ethoxy guanines. Each oligonucleotide had 2'-0-methyl A, C and U bases and all linkages were phosphorothiate. These oligonucleotides were purified, desalted, lyophilized, and dissolved at 300 A 260 per ml in sterile water. Samples were removed and diluted 1 :4 with 0.1 N HCl to give a final pH of approximately 1.5, and placed in a heat block at 39 ° C. Aliquots were taken at the times indicated and diluted 1:20 into 0.025 M NaOH, 0.03 M NaCl. The samples were run on an analytical HPLC under strongly denaturing conditions on an anion exchange column. The results of the oligonucleotide degradation are as follows, with percentage representing the oligonucleotides still present after exposure to acid: Sequence - cug uca ggg aga ac % Full length Time 0 2.5 hr 1 day 6 days DNA Gs 99 1 0 0 2'-0-methyl Gs 99 98 97.5 96 2' methoxy ethoxy Gs 99 99 95 76 Thus, the addition of a 2'-0-R group (e.g., 2'-0-methyl group) or a 2'-0-R-0-R group (e.g., a methoxy ethoxy group) to the 2' position of the unmodified sugar group significantly increased the stability of the phosphorothioate oligonucleotide molecule. EXAMPLE 12: Skin Penetration Study A study was conducted using cadaver skin comparing the ability of un-protonated and protonated end protected 2'-0-methyl RNA to be transported through the skin. The in vitro human cadaver skin model has proven to be a valuable tool for the study of percutaneous absoφtion and the determination of the pharmacokinetics of topically applied dmgs. The model uses human cadaver skin mounted in specially designed diffusion chambers which allow the skin to be maintained at a temperature and humidity that match typical in vivo conditions (Franz, J. Invest. Dermatol. 64: 190- 195, 1975). A finite dose (5-7 mg/cm 2 ) of formulation is applied to the outer surface of the skin and drag absoφtion is measured by monitoring its rate of appearance in the receptor solution bathing the inner surface of the skin. Data defining total absoφtion, rate of absoφtion, as well as skin content can be accurately determined in this model. The method has historic precedent for accurately predicting in vivo percutaneous absoφtion kinetics (Franz: "The finite dose technique is a valid in vitro model for the study of percutaneous absoφtion in man." In Skin: Drug Application and Evaluation of Environmental Hazards, Current Problems in Dermatology, vol.7, G. Simon, et al., Z. Paster, M. Klingberg. M. Kaye, (Eds), Basel, Switzerland, S. Karger, 1978, pp. 58-68). Three donors were evaluated. The applied concentration of the nucleic acids was 0.108 μglμL. Five μL of each nucleic acid were applied to a 0.8 cm 2 skin section. There was approximately a 400% greater transfer for the protonated oligo versus the unprotonated form. EXAMPLE 13: Efficacy in Topical Skin Bacterial Infections Human skin boils, called furuncles, were treated with protonated/acidified nucleic acids. A furuncle is a localized pyogenic infection typically originating in a hair follicle. A furuncle is a round, tender, pus-filled area of the skin, developing a white cap which will rapture if stressed. Often, a furuncle may be an infection of the hair follicle in the deepest section. A furuncle will normally heal in 10-25 days. Without treatment, furuncles usually must drain before they will heal. This most often occurs in just under 2 weeks. If the furuncle is a deep lesion, it may require systemic antibiotic therapy to eliminate the bacteria in addition to minor surgery to open the furuncle and drain the pus. In summary, furuncles are painful swellings of the skin caused by deep skin infection with bacteria that rarely resolve untreated in less than 10 days. Protonated/acidified nucleic acids have demonstrated efficacy in treating a 1.5 cm furuncle on the back of a 36-year-old male subject in good health. Within 8 hours, the protonated/acidified nucleic acids rapidly and dramatically relieved both the pain and swelling of the furuncle. Protonated/acidified nucleic acid (pH 1.5, sequence ACGCGCCATTAT, SEQ ID NO:3) was used to treat a 1.5 cm furuncle one day after its appearance. The nucleic acid consisted of 2'-0-methyl substituted ribonucleotides, phosphodiester linked, end blocked with an inverted T at both the 5' and 3' ends. Specifically, 100 μl of protonated/acidified nucleic acids (18.9 mM) dissolved in water was used to treat the 1.5 cm furuncle, which was raised, red and swollen, with a 2-3 mm pustule, and was very painfiil to the subject. After 8 hours of treatment, the furuncle had spontaneously drained and was significantly reduced to approximately 0.5 cm in size with a concurrent reduction in swelling and redness. The subject's pain was significantly alleviated. A second 50 μl application of protonated/acidified nucleic acids was applied at this time. After 16 hours from the initial treatment, there was virtually no swelling, pain, or inflammation. A small pinkish area of <0.5 cm remained from the original furuncle. A final application of protonated/acidified nucleic acids was applied, 24 hours post treatment of the infection, to continue accelerating the healing process. The residual vestiges of the furuncle healed entirely after the third application and within a day. In conclusion, protonated/acidified nucleic acids have been demonstrated to be very effective in rapidly treating a Staphylococcal furuncle using water as the transport medium. Protonated/acidified nucleic acids were particularly effective in rapidly resolving both the pain and swelling of the furuncle. EXAMPLE 14: Efficacy in Topical Treatment of Ear Infections Protonated/acidified nucleic acids were very effective in treating outer ear epidermal infections in chinchillas caused by Pseudomonas aeruginosa bacteria. All the chinchilla infected ears that received continued protonated/acidified nucleic acid treatment were completely cured 4 days after treatment began. Chinchillas' ears were infected with Pseudomonas aeruginosa bacteria. Specifically, the maceration of the epidermal layer of the chinchillas' ears was caused by prolonged exposure of the ears to water. This helped create an environment for the Pseudomonas infection in the epidermal layer of skin lining in the chinchillas' ear canals. Cotton plegets were saturated with a suspension of washed Pseudomonas aeruginosa and were inserted in the ear canals of the chinchillas. The plegets were removed after 48 hours. Treatment of the chinchillas began on day 3 post infection, when the ears were judged to have a "level 3" severity as determined by otoscopic examination. The chinchillas received two daily topical applications of either 400 μl of protonated/acidified nucleic acids at pH 1.5 of sequence SEQ ID NO: 3 in water (2.8 mM), or 400 μl of the protonated/acidified nucleic acids of identical sequence (2 mM) in a vehicle mixture (water/ethanol/propylene glycol). The nucleic acid consisted of 2'-0-methyl substituted ribonucleotides, phosphodiester linked and end blocked with butanol at both the 5' and 3' ends. The chinchillas were examined daily to assess the effectiveness of treatment based on the degree of severity of the ear infections. The results of the protonated/acidified nucleic acid treatment indicated that all of the treated chinchillas' ears showed a significant reduction in the severity of ear infections, as determined by otoscopic examination. Significant improvements occurred after 3 treatments of protonated/acidified nucleic acids. The chinchillas were either sacrificed or continued treatment for an additional 4 to 5 days. Untreated control chinchillas showed no improvement over this time frame. In contrast, all ear infections that received continued protonated/acidified nucleic acids treatment were completely cured by day 7 post infection (i.e., 4 days after treatment began with protonated/acidified nucleic acids). In addition, there were slight differences in the progression of healing between protonated/acidified nucleic acids dissolved in the two transport mediums; water or the vehicle mixture (water/ethanol/propylene glycol). Based on otoscopic examination, protonated/acidified nucleic acids in the vehicle mixture were slightly more effective in treating the ear infections. In conclusion, protonated/acidified nucleic acids have demonstrated effectiveness in treating chinchillas' outer ear infections caused by Pseudomonas aeruginosa. This is significant since this infectious bacteria is naturally an antibiotic-resistant bacteria. EXAMPLE 15: Efficacy of Protonated/Acidified Nucleic Acid in Treatment of Strep, pyogenes Skin Infection on a Dog A 135 1b. 2 year old, female Newfoundland had sustained a cut on her abdomen and developed a Strep, pyogenes infection. The area was swollen, inflamed and painful to the touch. Treatment with Neosporin® (Warner-Lambert, Co.) for 3 days failed to produce any improvement. Two treatments separated by 12 hours directly to the injury with 2'-0-methyl substituted ribonucleotides that were phosphodiester linked, pH 1.5, end blocked with butanol at both the 5' and 3' ends, with sequence of SEQ ID NO: 3, completely cleared up the infection, swelling, inflammation, and sensitivity to touch. EXAMPLE 16: Protonated/Acidified Nucleic Acid Efficacy in a Topical Pseudomonas Bum Model of Infection Protonated/acidified nucleic acids have demonstrated efficacy in treating topical skin infections in immuno-compromised mice. Mice were treated with cyclophosphamide (200 mg/kg, I.P.) in advance of a burn to the skin to inhibit their immune systems. Three days later burns were induced, followed by application of 109 CFU of Pseudomonas aeruginosa topically applied to the bum site to create an infection. Treatment with nucleic acid occurred at 4 hrs. and 8 hrs. post infection. The nucleic acid used in the experiment was at pH 1.5, had the sequence SEQ ID NO:3, and consisted of 2'-0-methyl substituted ribonucleotides, phosphodiester linked and end blocked with butanol at both the 5' and 3' ends. Ninety percent (90%) of the treated animals survived and were free of systemic Pseudomonas infections while 90% of the control animals developed systemic infections and died. The protonated/acidified nucleic acid was able to cure the topical infection. In addition, topical application of nucleic acid was able to prevent the topical Pseudomonas infection from progressing to a fatal, systemic infection. EXAMPLE 17: Protonated/Acidified Nucleic Acid Efficacy in a Systemic Pseudomonas Bum Model of Infection Mice were treated S.C. with 10 6 or 10 7 CFU of Pseudomonas aeruginosa after induction of a skin bum. Two hours post infection, treatment was initiated with acidified nucleic acid. Forty percent of the dose was administered IN. with the remainder given S.C. The nucleic acid used in the experiment was at pH 1.5, had the sequence SEQ ID NO:3, and consisted of 2'-0-methyl substituted ribonucleotides, phosphodiester linked and end blocked with butanol at both the 5' and 3' ends. The procedure was repeated 6 hrs. later. Additional subcutaneous injections were given twice daily on day two and three. All but one of the 45 control animals died, and 94% of the 35 treated mice survived and were healthy. These treated, healthy mice were sacrificed and checked for sepsis. Pseudomonas bacteria were not detected in the spleen, liver, or blood. In conclusion, a protonated/acidified nucleic acid was 94% effective at treating a systemic Pseudomonas infection that would have been fatal if left untreated. EXAMPLE 18 : B Cell Mediated Dermatitis An anti-inflammatory oligonucleotide, OE-2a has the sequence CGTGTCAGGAGAAC (SEQ ID NO:l), consists of 2'-0-methyl substituted ribonucleotides, and has 5' and 3' ends blocked with inverted Ts. OE-2a was targeted against the human PDE4 gene was dissolved at 35 mg/ml (7.7 μMolar) in water at approximately pH 3 and used to treat a 37 year old male with a history of severe recurrent atopic dermatitis. The dermatitis was specifically eradicated with OE-2a. In addition, future occurrences of atopic dermatitis have been completely eliminated. A 37 year old male presented with severe atopic dermatitis, completely covering the inside of both forearms. Atopic dermatitis is a chronic disorder characterized by intensely pruritic inflamed papules. The inflammatory response is associated with over-production of IgE by B lymphocytes. Higher levels of PDE4 have been reported for individuals with atopic dermatitis. An antisense oligonucleotide, OE-2a, specifically targeted to PDE4 was applied to a 2" by 3" segment of the left forearm. A second oligo, OE-1, was applied to another segment of the same arm. OE-1 has a similar base distribution to OE-2a, but is homologous to a bacterial gene. Oligonucleotides were applied twice at 12 hour intervals. OE-2a was successful at clearing the dermatitis on the area to which it was applied. OE-1 had no effect. The patient commented prior to the second treatment that the itching had stopped on the area corresponding to treating with the OE-2a after about 6 hours. Treatment on the second arm was initiated at this time exclusively with OE-2a. Again there were 2 treatments 12 hours apart. Again the patient remarked that all itching had ceased within 6 hours. The dermatitis was completely cleared within 12 hours of the second treatment. There have been no recurrences of atopic dermatitis on this individual from February through December, although he typically suffers from recurring bouts during the heat of the summer. EXAMPLE 19: T Cell Mediated Dermatitis OE-2a at 35 mg/ml (7.7 μMolar) in water at approximately pH 3 was used to treat a case of T cell mediated contact dermatitis triggered by poison ivy. The dermatitis was completely eliminated with 2 treatments that also prevented secondary eruptions on other areas of the infected individual. A female presented with poison ivy on several areas of the bottom of her foot. The patient complained of itching that is associated with T cell mediated type hypersensitivity. The contact dermatitis was characterized by redness, induration, and vesiculation. The anti-inflammatory oligo OE-2a was applied to the bottom of the foot. Within 12 hours the patient noted that the intense itching had ceased. A second application of OE-2a resulted in a disappearance of the redness, induration, and vesiculation. It is of interest to note that topical application of OE-2a not only eliminated the visible poison ivy on the bottom of the foot, but also prevented any additional eruptions of poison ivy induced dermatitis elsewhere on the individual. EXAMPLE 20: Acute Wheal and Flare Reaction OE-2a at 43.6 mg/ml (7.7 μMolar) and approximately pH 7 was able to prevent both an immediate and delayed-type hypersensitivity response when applied within minutes of receiving multiple wasp stings. A female patient with a history of severe wheal and flare skin reaction in response to insect bites presented with an arm that had received multiple wasp stings. The patient was in severe pain and hysterical. OE-2a was administered immediately. Within 5 minutes the patient was calm and pain free. Remarkably, administration of the OE-2a within 5 minutes of receiving the stings completely prevented any immediate wheal and flare reaction, as well as any delayed reaction. EXAMPLE 21: Chemically Induced Dermatitis OE-2a was successfully used to treat a case of chemically induced contact dermatitis that had failed to respond to standard dermatological treatments. A 59 year old woman presented with a case of contact dermatitis on her neck triggered by a reaction to dry cleaning reagents in a turtleneck sweater. Over the course of a month she had been treated by a dermatologist with cortisone, antibiotics, and a variety of other topical drugs. The various treatments gave no more than temporary sporadic relief and they failed to eliminate the itching and redness. At this time the patient was treated topically with OE-2a. The itching and redness disappeared completely after two treatments with no recurrences over a 5 month period. EXAMPLE 22: Toxicity - Skin Level and Whole Animal Evaluations were made to determine protonated/acidified nucleic acids' toxicity. Based on this initial research, it has been determined that protonated/acidified nucleic acids are not toxic. Methodology Forty-five animals (mice, male/C57 Balb/c) received protonated/acidified nucleic acid treatment subcutaneous, intraperitoneal injection, or topical application. The mice were randomly chosen and were approximately 6 to 8 weeks of age at study commencement (25-30 gm. body weight). The mice were housed five to a box and maintained in an environmentally controlled room with free access to food and water. The mice (five per group) were injected daily for 14 days with a protonated/acidified nucleic acid at pH 1.5 of sequence SEQ ID NO: 3, or water. The nucleic acid consisted of 2'-0-methyl substituted ribonucleotides, phosphodiester linked, end blocked with butanol at both the 5' and 3' ends. Treatment was via I.P. route, subcutaneous route, or topical (as noted below). All mice were observed daily for viability and signs of toxicity during the treatment period. Necropsies were performed 24 hours after the last injection. At necropsy, a complete examination of all body cavities and organs was conducted. Selected organs were fixed and stained for histopathological evaluation. The summary of the findings are as follows. Mortality and Clinical Manifestations During the study, all mice remained fully active and alert with no clinical signs of abnormal behavior, even at a dose of 100 mg/kg. The LD 50 for the oligonucleotides of this invention is shown to be greater than 400 mg/kg of the body weight in mice. Clinical Chemistry Among all the clinical chemistry parameters tested, there were no abnormalities in liver enzymes (alkaline phosphatase, ALT, AST) and total bilirubin level. Mean serum alkaline phosphatase, ALT and ASL levels showed no significant differences from the vehicle control values, suggesting that there is no evidence of toxicosis. The indirect and direct bilirubin values showed no differences from vehicle-treated controls, indicating no renal or hepatic abnormalities. Gross Necropsy During the study, observation determined that there was nothing grossly evident at the site of injection suggesting no local inflammatory reactions associated with even the highest dose of nucleic acid. There were no visible signs of enlargement or necropsy of any organs. Specifically, there was no enlargement of the spleen, liver or kidneys as compared to those of the control animals, even at doses of 100 mg/kg per day administered for 14 consecutive days. Histological examination of slides prepared from different tissues showed no differences between the treated and control animals. In summary, the key results were: (1) There were no significant increases in any enzyme level in the treated group vs. control group; (2) There were no signs of gross abnormalities in any of the animals treated with oligos; (3) All animals remained healthy and alert throughout the study; and (4) All routes (intraperitoneal, subcutaneous, topical) provided similar results. The results indicated that the protonated/acidified nucleic acids were non-toxic even after 14 days of daily administration of 100 mg per kilogram and regardless of the route of administration. While the present invention has been described with reference to the specific embodiments thereof, it should be imderstood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process, process step or steps, to the objective, spirit and scope of the present invention. All such modifications are intended to be within the scope of the claims appended hereto.

Claims: WHAT IS CLAIMED IS: 1. A polymer comprising: one or more nucleotides having a nucleic acid backbone structure modified from that of a naturally occurring nucleotide; and a blocking chemical modification at or near at least one end of the polymer. 2. The polymer of claim 1, wherein the nucleic acid is a polymer comprised of a plurality of nucleotides. 3. The polymer of claim 2, wherein the nucleic acid is an oligonucleotide having about 2 to about 100 nucleotides. 4. The polymer of claim 1 , wherein the nucleic acid is a monomer. 5. The polymer of claim 1 , wherein the nucleic acid is comprised of a blocking chemical modification at or near the 3' end of the nucleic acid. 6. The polymer of claim 1 or 5, wherein the nucleic acid is comprised of a blocking chemical modification at or near the 5' end of the nucleic acid. 7. The polymer of claim 1 , wherein the blocking chemical modification is one or more moiety selected from the group consisting of: inverted sugars, inverted nucleotides, dideoxynucleotides, fluorescein, psoralen, acridine, dinitrophenyl, methyl phosphonate, an alkyl group, an alcohol group, an aryl group, a 3'-0-methyl ribonucleotide, a 3'-0-alkyl ribonucleotide, a 2'-0-alkyl phosphorothioate, a 2'-0-alkyl-n(0-alkyl) phosphorothioate, a 3'-0-alkyl phosphorothioate, a 3'-0- alkyl-n(O-alkyl) phosphorothioate, a hexa-ethyloxy-glycol, cordycepin, cytosine arabanoside, 2'- methoxy-ethoxy nucleotides, phosphoramidates, a peptide linkage, cholesterol, biotin, rhodamine, glyceryl, butyl, hexanol, and butanol. 8. The polymer of claim 1 , wherein the backbone structure includes one or more of the group consisting of: 2'-halogens, 2'-0-methyl, 2'-0-alkyl, 2'-0-alkyl-n(0-alkyl), 3'-halogens, 3'-0- alkyl, 3'-0-alkyl-n(0-alkyl), phosphodiester linkages, phosphotriester linkages, phosphoramidate linkages, siloxane linkages, carbonate linkages, carboxymethylester linkages, acetamidate linkages, carbamate linkages, thioether linkages, bridged phosphoramidate linkages, bridged methylene phosphonate linkages, phosphorothioate linkages, methylphosphonate linkages, phosphorodithioate linkages, moφholino, bridged phosphorothioate linkages, sulfone intemucleotide linkages, 3'-3' linkages, 5'-2' linkages, 5'-5' linkages, 2'-deoxy-erythropentofuranosyl, 2'-fluoro, 2'-0-alkyl nucleotides, 2'-0-alkyl-n(0-alkyl) phosphodiesters, moφholino linkages, p-ethoxy oligonucleotides, PNA linkages, p-isopropyl oligonucleotides, or phosphoramidates, sulfide linkages, sulfoxide linkages, sulfamate linkages, sulfamide linkages, formacetal/ ketal linkages, thioformacetal linkages, chiral phosphorous linkages, aminoalkylphosphorothioamidate linkages, and four residue group linkages. 9. A pharmaceutical composition comprised of: a polymer including one or more nucleotides having a nucleic acid backbone structure modified from that of a naturally occurring nucleotide and a blocking chemical modification at or near at least one end of the polymer; and a pharmaceutically acceptable carrier. 10. The pharmaceutical composition of claim 9, wherein the polymer is encapsulated in a liposome. 11. A method for modulating a physiological process in a cell comprising: contacting said cell with a polymer comprising: at least one nucleotide having a nucleic acid backbone structure modified from that of a naturally occurring nucleotide; and a blocking chemical modification at or near at least one end of the polymer. 12. A polymer including the following general structure: A-(B) n -C wherein B includes at least one nucleotide from the group consisting of a 2'-0-alkyl nucleotide, a 2'-0-alkyl-n(0-alkyl) nucleotide, a 3'-0-alkyl nucleotide, and 3'-0-alkyl-n(0-alkyl) nucleotide; n is an integer of from 1 to 98; A is a 5' end blocking group and C is a 3' end blocking group.

Inventors: ARROW AMY, DALE RODERIC M K, GATTON STEVEN L, ARROW, AMY, DALE, RODERIC, M., K., GATTON, STEVEN, L.
Applicants: ARROW AMY, DALE RODERIC M K, GATTON STEVEN L, OLIGOS ETC INC, ARROW, AMY, DALE, RODERIC, M., K., GATTON, STEVEN, L., OLIGOS ETC. INC.
Application year: 1999
Main classification: C07H21
IPC codes: A61K9, A61K31, A61K47, A61K48, A61P3, A61P17, A61P29, A61P31, A61P35, C07H21, C12N5, C12N15