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Antiviral oligonucleotides having a conserved g4 core sequenceRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), O-glycoside, , Nitrogen Containing Hetero Ring, Polynucleotide (e.g., Rna, Dna, Etc.)Antiviral oligonucleotides having a conserved g4 core sequence description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070015723, Antiviral oligonucleotides having a conserved g4 core sequence. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS REFERENCE TO RELATED APPLICATIONS [0001] The present application is a continuation of U.S. application Ser. No. 08/403,888 filed Jun. 12, 1995, which is the national phase of PCT Application Serial No. PCT/US93/09297 filed Sep. 29, 1993, which is a continuation-in-part of U.S. application Ser. No. 07/954,185 filed Sep. 29, 1992, now abandoned, each of which is incorporated herein by reference in its entirety. FIELD OF THE INVENTION [0002] This invention relates to the design and synthesis of oligonucleotides which can be used to inhibit the activity of viruses in vivo or in vitro and to treat viral-associated disease. These compounds can be used either prophylactically or therapeutically for diseases associated with viruses such as HIV, HSV, HCMV and influenza. Oligonucleotides capable of inhibiting phospholipase A.sub.2 enzyme activity are also provided which may be useful for the treatment of inflammatory disorders, as well as neurological conditions. Oligonucleotides designed for the treatment of cancer and to retard aging are also contemplated by this invention. BACKGROUND OF THE INVENTION Antivirals [0003] There have been many approaches for inhibiting the activity of viruses such as the human immunodeficiency virus (HIV), herpes simplex virus (HSV), human cytomegalovirus (HCMV) and influenza. Such prior art methods include nucleoside analogs (e.g., HSV) and antisense oligonucleotide therapies (e.g., HIV, influenza). [0004] Prior attempts to inhibit HIV by various approaches have been made by a number of researchers. For example, Zamecnik and coworkers have used phosphodiester antisense oligonucleotides targeted to the reverse transcriptase primer site and to splice donor/acceptor sites, P. C. Zamecnik, J. Goodchild, Y. Taguchi, P. S. Sarin, Proc. Natl. Acad. Sci. USA 1986, 83, 4143. Goodchild and coworkers have made phosphodiester antisense compounds targeted to the initiation sites for translation, the cap site, the polyadenylation signal, the 5' repeat region, primer binding site, splice sites and a site between the gag and pol genes. J. Goodchild, S. Agrawal, M. P. Civeira, P. S. Sarin, D. Sun, P. C. Zamecnik, Proc. Natl. Acad. Sci. U.S.A. 1988, 85, 5507; U.S. Pat. No. 4,806,463. Agrawal and coworkers have used chemically modified antisense oligonucleotide analogs targeted to the cap and splice donor/acceptor sites. S. Agrawal, J. Goodchild, M. P. Civeira, A. H. Thornton, P. S. Sarin, P. C. Zamecnik, Proc. Nat'l. Acad. Sci. USA 1988, 85, 7079. Agrawal and coworkers have used antisense oligonucleotide analogs targeted to the splice donor/acceptor site inhibit HIV infection in early infected and chronically infected cells. S. Agrawal, T. Ikeuchi, D. Sun, P. S. Sarin, A. Konopka, J. Maizel, Proc. Natl. Acad. Sci. U.S.A. 1989, 86, 7790. [0005] Sarin and coworkers have also used chemically modified antisense oligonucleotide analogs targeted to the HIV cap and splice donor/acceptor sites. P. S. Sarin, S. Agrawal, M. P. Civeira, J. Goodchild, T. Ikeuchi, P. C. Zamecnik, Proc. Natl. Acad. Sci. U.S.A. 1988, 85, 7448. Zaia and coworkers have also used an antisense oligonucleotide analog targeted to a splice acceptor site to inhibit HIV. J. A. Zaia, J. J. Rossi, G. J. Murakawa, P. A. Spallone, D. A. Stephens, B. E. Kaplan, J. Virol. 1988, 62, 3914. Matsukura and coworkers have synthesized antisense oligonucleotide analogs targeted to the initiation of translation of the HIV rev gene mRNA. M. Matsukura, K. Shinozuka, G. Zon, Proc. Natl. Acad. Sci. USA 1987, 84, 7706; R. L. Letsinger, G. R. Zhang, D. K. Sun, T. Ikeuchi, P. S. Sarin, Proc. Natl. Acad. Sci. U.S.A. 1989, 86, 6553. Mori and coworkers have used a different antisense oligonucleotide analog targeted to the same region as Matsukura. K. Mori, C. Boiziau, C. Cazenave, Nucleic Acids Res. 1989, 17, 8207. Shibahara and coworkers have used antisense oligonucleotide analogs targeted to a splice acceptor site as well as the reverse transcriptase primer binding site. S. Shibahara, S. Mukai, H. Morisawa, H. Nakashima, S. Kobayashi, N. Yamamoto, Nucl. Acids Res. 1989, 17, 239. Letsinger and coworkers have synthesized and tested a oligonucleotide analogs with conjugated cholesterol targeted to a splice site. K. Mori, C. Boiziau, C. Cazenave, Nucleic Acids Res. 1989, 17, 8207. Stevenson and Iversen have conjugated polylysine to antisense oligonucleotide analogs targeted to the splice donor and the 5'-end of the first exon of the HIV tat gene. M. Stevenson, P. L. Iversen, J. Gen. Virol. 1989, 70, 2673. Buck and coworkers have described the use of phosphate-methylated DNA oligonucleotides targeted to HIV mRNA and DNA. H. M. Buck, L. H. Koole, M. H. P. van Gendersen, L. Smith, J. L. M. C. Green, S. Jurriaans and J. Goudsmit, Science 1990, 248, 208-212. [0006] These prior attempts at inhibiting HIV activity have largely focused on the nature of the chemical modification used in the oligonucleotide analog. Although each of the above publications have reported some degree of success in inhibiting some function of the virus, a general therapeutic scheme to target HIV and other viruses has not been found. Accordingly, there has been and continues to be a long-felt need for the design of compositions which are capable of effective, therapeutic use. [0007] Currently, nucleoside analogs are the preferred therapeutic agents for herpes (HSV) infections. A number of pyrimidine deoxyribonucleoside compounds have a specific affinity for the virus-encoded thymidine (dCyd) kinase enzyme. The specificity of action of these compounds confines the phosphorylation and antiviral activity of these compounds to virus-infected cells. A number of drugs from this class, e.g., 5-iodo-dUrd (IDU), 5-trifluoro-methyl-dUrd (FMAU), 5-ethyl-dUrd (EDU), (E)-5-(2-bromovinyl)-dUrd (BVDU), 5-iodo-dCyd (IDC), and 5-trifluoromethyl-dUrd (TFT), are either in clinical use or likely to become available for clinical use in the near future. IDU is a moderately effective topical antiviral agent when applied to HSV gingivostomatitis and ocular stromal keratitis; however, its use in controlled clinical studies of HSV encephalitis revealed a high toxicity associated with IDU treatment. Although the antiviral specificity of 5-arabinofuranosyl cytosine (Ara-C) was initially promising, its clinical history has paralleled that of IDU. The clinical appearance of HSV strains which are deficient in their ability to synthesize the viral thymidine kinase has generated further concern over the future efficacy of this class of compounds. [0008] The utility of a number of viral targets has been defined for anti-HSV compound development. Studies with thiosemicarbazone compounds have demonstrated that inhibition of the viral ribonucleotide reductase enzyme is an effective means of inhibiting replication of HSV in vitro. Further, a number of purine nucleosides which interfere with viral DNA replication have been approved for treatment of human HSV infections. 9-(.beta.-D-arabinofuranosyl)adenine (Ara-A) has been used for treatment of HSV-1 keratitis, HSV-1 encephalitis and neonatal herpes infections. Reports of clinical efficacy are contradictory and a major disadvantage for practical use is the extremely poor solubility of Ara-A in water. 9-(2-hydroxyethoxymethyl)guanine (Acyclovir, ACV) is of major interest. In humans, ACV has been used successfully in the therapy of localized and disseminated HSV infections. However there appear to be both the existence of drug-resistant viral mutants and negative results in double-blind studies of HSV-1 treatment with ACV. ACV, like Ara-A, is poorly soluble in water (0.2%) and this physical characteristic limits the application forms for ACV. The practical application of purine nucleoside analogs in an extended clinical situation suffers from their inherently efficient catabolism, which not only lowers the biological activity of the drug but also may result in the formation of toxic catabolites. [0009] The effective anti-HSV compounds currently in use or clinical testing are nucleoside analogs. The efficacy of these compounds is diminished by their inherently poor solubility in aqueous solutions, rapid intracellular catabolism and high cellular toxicities. An additional caveat to the long-term use of any given nucleoside analogue is the recent detection of clinical isolates of HSV which are resistant to inhibition by nucleoside compounds which were being administered in clinical trials. Antiviral oligonucleotides offer the potential of better compound solubilities, lower cellular toxicities and less sensitivity to nucleotide point mutations in the target gene than those typical of the nucleoside analogs. [0010] Effective therapy for cytomegalovirus (CMV) has not yet been developed despite studies on a number of antivirals. Interferon, transfer factor, adenine arabinoside (Ara-A), acycloguanosine (Acyclovir, ACV) and certain combinations of these drugs have been ineffective in controlling CMV infection. Based on preclinical and clinical data, foscarnet (PFA) and ganciclovir (DHPG) show limited potential as antiviral agents. PFA treatment has resulted in the resolution of CMV retinitis in five AIDS patients. DHPG studies have shown efficacy against CMV retinitis or colitis. DHPG seems to be well tolerated by treated individuals, but the appearance of a reversible neutropenia, the emergence of resistant strains of CMV upon long-term administration, and the lack of efficacy against CMV pneumonitis limit the long term applications of this compound. The development of more effective and less-toxic therapeutic compounds and methods is needed for both acute and chronic use. [0011] Classical therapeutics has generally focused upon interactions with proteins in efforts to moderate their disease-causing or disease-potentiating functions. Such therapeutic approaches have failed for cytomegalovirus infections. Therefore, there is an unmet need for effective compositions capable of inhibiting cytomegalovirus activity. [0012] There are several drugs available which have some activity against the influenza virus prophylactically. None, however, are effective against influenza type B. Moreover, they are generally of very limited use therapeutically and have not been widely used in treating the disease after the onset of symptoms. Accordingly, there is a world-wide need for improved therapeutic agents for the treatment of influenza virus infections. [0013] Prior attempts at the inhibition of influenza virus using antisense oligonucleotides have been reported. Leiter and co-workers have targeted phosphodiester and phosphorothioate oligonucleotides to influenza A and influenza C viruses. Leiter, J., Agrawal, S., Palese, P. & Zamecnik, P. C., Proc. Natl. Acad. Sci. USA; 1990, 87, 3430-3434. These workers targeted the polymerase PB1 gene and mRNA in the vRNA 3' region and mRNA 5' region, respectively. Sequence-specific inhibition of influenza A was not observed although some specific inhibition of influenza C was noted. [0014] Zerial and co-workers have reported inhibition of influenza A virus by oligonucleotides coincidentally linked to an intercalating agent. Zerial, A., Thuong, N. T. & Helene, C., Nucleic Acids Res. 1987, 57, 9909-9919. Zerial et al. targeted the 3' terminal sequence of 8 vRNA segments. Their oligonucleotide analog was reported to inhibit the cytopathic effects of the virus in cell culture. [0015] Kabanov and co-workers have synthesized an oligonucleotide complementary to the loop-forming site of RNA encoding RNA polymerase 3. Kabanov, A. V., Vinogradov, S. V., Ovcharenko, A. V., Krivonos, A. V., Melik-Nubarov, N. S., Kiselev, V. I., Severin, E. S., FEB; 1990, 259, 327-330. Their oligonucleotide was conjugated to a undecyl residue at the 5' terminal phosphate group. They found that their oligonucleotide inhibited influenza A virus infection in MDCK cells. [0016] Although each of the foregoing workers reported some degree of success in inhibiting some function of an influenza virus, a general therapeutic scheme to target influenza viruses has not been found. Moreover, improved efficacy is required in influenza virus therapeutics. Accordingly, there has been and continues to be a long-felt need for the design of oligonucleotides which are capable of effective therapeutic use. Phospholipase A.sub.2 Enzyme Activity [0017] Phospholipase A.sub.2 is a family of lipolytic enzymes which hydrolyze membrane phospholipids. Phospholipase A.sub.2 catalyzes the hydrolysis of the sn-2 bond of phospholipids resulting in the production of free fatty acid and lysophospholipids. Several types of phospholipase A.sub.2 enzymes have been cloned and sequenced from human cells. However, there is biochemical evidence that additional forms of phospholipase A.sub.2 exists. Mammalian secreted phospholipase A.sub.2 shares strong sequence similarities with phospholipase A.sub.2 isolated from the venom of poisonous snakes. Secreted forms of phospholipase A.sub.2 have been grouped into two categories based upon the position of cysteine residues in the protein. Type I phospholipase A.sub.2 includes enzymes isolated from the venoms of Elapidae (cobras), Hydrophidae (sea snakes) and the mammalian pancreatic enzyme. Type II phospholipase A.sub.2 includes enzymes isolated from the venoms of Crotalidae (rattlesnakes and pit vipers), Viperidae (old world vipers) and an enzyme secreted from platelets and other mammalian cells. [0018] Much interest has been generated in mammalian type II phospholipase A.sub.2, in that elevated concentrations of the enzyme have been detected in a variety of inflammatory disorders including rheumatoid arthritis, inflammatory bowel disease, and septic shock as well as neurological conditions such as schizophrenia, Pruzanski, W., Keystone, E. C., Stemby, B., Bombardier, C., Snow, K. M., and Vadas, P. J. Rheumatol. 1988, 15, 1351; Pruzanski and Vadas J. Rheumatol. 1988, 15, 11; Oliason, G., Sjodahl, R., and Tagesson, C. Digestion 1988, 41, 136; Vadas et al. Crit. Care Med. 1988, 16, 1; Gattaz, W. F., Hubner, C. v.K., Nevalainen, T. J., Thuren, T., and Kinnunen, P. K. J. Biol. Psychiatry 1990, 28, 495. It has been recently demonstrated that secretion of type II phospholipase A.sub.2 is induced by a variety of proinflammatory cytokines such as interleukin-1, interleukin 6, tumor necrosis factor, interferon-.gamma., and bacterial lipopolysaccharide. Hulkower, K., Hope, W. C., Chen, T., Anderson, C. M., Coffey, J. W., and Morgan, D. W., Biochem. Biophys. Res. Comm. 1992, 184, 712; Crowl, R. M., Stoller, T. J., Conroy, R. R. and Stoner, C. R., J. Biol. Chem. 1991, 266, 2647; Schalkwijk, C., Pfeilschafter, J., Marki, F., and van den Bosch, J., Biochem. Biophys. Res. Comm. 1991, 174, 268; Gilman, S. C. and Chang, J., J. Rheumatol. 1990, 17, 1392; Oka, S. and Arita, H., J. Biol. Chem. 1991, 266, 9956. Anti-inflammatory agents such as transforming growth factor-.beta. and glucocorticoids have been found to inhibit secretion of type II phospholipase A.sub.2. Oka, S. and Arita, H., J. Biol. Chem. 1991, 266, 9956; Schalkwijk, C., Pfeilschifter, J., Marki, F. and van den Bosch, H., J. Biol. Chem. 1992, 267, 8846. Type II phospholipase A.sub.2 has been demonstrated to be secreted from a variety of cell types including platelets, chrondrocytes, synoviocytes, vascular smooth muscle cells, renal mesangial cells, and keratinocytes. Kramer, R. M., Hession, C., Johansen, B., Hayes, G., McGray, P., Chow, E. P., Tizard, R. and Pepinsky, R. B., J. Biol. Chem. 1989, 264, 5768; Gilman, S. C. and Chang, J., J. Rheumatol. 1990, 17, 1392; Gilman, S. C., Chang, J., Zeigler, P. R., Uhl, J. and Mochan, E., Arthritis and Rheumatol. 1988, 31, 126; Nakano, T., Ohara, O., Teraoka, H. and Arita, H., FEBS Lett., 1990, 261, 171; Schalkwijk, C., Pfeilschifter, J., Marki, F. and van den Bosch, H. Biochem. Biophys. Res. Comm. 1991, 174, 268. [0019] A role of type II phospholipase A.sub.2 in promoting some of the pathophysiology observed in chronic inflammatory disorders was suggested because direct injection of type II phospholipase A.sub.2 produced profound inflammatory reactions when injected intradermally or in the articular space in rabbits, Pruzanski, W., Vadas, P., Fomasier, V., J. Invest. Dermatol. 1986, 86, 380-383; Bomalaski, J. S., Lawton, P., and Browning, J. L., J. Immunol. 1991, 146, 3904; Vadas, P., Pruanski, W., Kim, J. and Formasier, V., Am. J. Pathol. 1989, 134, 807. Denaturation of the protein prior to injection was found to block the proinflammatory activity. Continue reading about Antiviral oligonucleotides having a conserved g4 core sequence... 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