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Antisense antiviral compound and method for treating influenza viral infectionRelated 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.)Antisense antiviral compound and method for treating influenza viral infection description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070004661, Antisense antiviral compound and method for treating influenza viral infection. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] This is a continuation-in-part of U.S. patent application Ser. No. 11/259,434, filed Oct. 25, 2005, which claims the benefit of priority to U.S. Provisional Application No. 60/622,077, filed Oct. 26, 2004. Both applications are incorporated herein by reference. FIELD OF THE INVENTION [0002] The invention relates to antisense oligonucleotide compounds for use in treating an influenza virus infection and antiviral treatment methods employing the compounds. REFERENCES [0003] Agrawal, S., S. H. Mayrand, et al. (1990). "Site-specific excision from RNA by RNase H and mixed-phosphate-backbone oligodeoxynucleotides." Proc Natl Acad Sci USA 87(4): 1401-5. [0004] Blommers, M. J., U. Pieles, et al. (1994). "An approach to the structure determination of nucleic acid analogues hybridized to RNA. NMR studies of a duplex between 2'-OMe RNA and an oligonucleotide containing a single amide backbone modification." Nucleic Acids Res 22(20): 4187-94. [0005] Bonham, M. A., S. Brown, et al. (1995). "An assessment of the antisense properties of RNase H-competent and steric-blocking oligomers." Nucleic Acids Res 23(7): 1197-203. [0006] Boudvillain, M., M. Guerin, et al. (1997). "Transplatin-modified oligo(2'-O-methyl ribonucleotide)s: a new tool for selective modulation of gene expression." Biochemistry 36(10): 2925-31. [0007] Cox, N. J. and K. Subbarao (1999). "Influenza." Lancet 354(9186): 1277-82. [0008] Cox, N. J. and K. Subbarao (2000). "Global epidemiology of influenza: past and present." Annu Rev Med 51: 407-21. [0009] Cross, C. W., J. S. Rice, et al. (1997). "Solution structure of an RNA.times.DNA hybrid duplex containing a 3'-thioformacetal linker and an RNA A-tract." Biochemistry 36(14): 4096-107. [0010] Dagle, J. M., J. L. Littig, et al. (2000). "Targeted elimination of zygotic messages in Xenopus laevis embryos by modified oligonucleotides possessing terminal cationic linkages." Nucleic Acids Res 28(10): 2153-7. [0011] Ding, D., S. M. Grayaznov, et al. (1996). "An oligodeoxyribonucleotide N3'->P5' phosphoramidate duplex forms an A-type helix in solution." Nucleic Acids Res 24(2): 354-60. [0012] Egholm, M., O. Buchardt, et al. (1993). "PNA hybridizes to complementary oligonucleotides obeying the Watson-Crick hydrogen-bonding rules." Nature 365(6446): 566-8. [0013] Felgner, P. L., T. R. Gadek, et al. (1987). "Lipofection: a highly efficient, lipid-mediated DNA-transfection procedure." Proc Natl Acad Sci USA 84(21): 7413-7. [0014] Gait, M. J., A. S. Jones, et al. (1974). "Synthetic-analogues of polynucleotides XII. Synthesis of thymidine derivatives containing an oxyacetamido- or an oxyformamido-linkage instead of a phosphodiester group." J Chem Soc [Perkin 1] 0(14): 1684-6. [0015] Gee, J. E., I. Robbins, et al. (1998). "Assessment of high-affinity hybridization, RNase H cleavage, and covalent linkage in translation arrest by antisense oligonucleotides." Antisense Nucleic Acid Drug Dev 8(2): 103-11. [0016] Lesnikowski, Z. J., M. Jaworska, et al. (1990). "Octa(thymidine methanephosphonates) of partially defined stereochemistry: synthesis and effect of chirality at phosphorus on binding to pentadecadeoxyriboadenylic acid." Nucleic Acids Res 18(8): 2109-15. [0017] Mertes, M. P. and E. A. Coats (1969). "Synthesis of carbonate analogs of dinucleosides. 3'-Thymidinyl 5'-thymidinyl carbonate, 3'-thymidinyl 5'-(5-fluoro-2'-deoxyuridinyl) carbonate, and 3'-(5-fluoro-2'-deoxyuridinyl) 5'-thymidinyl carbonate." J Med Chem 12(1): 154-7. [0018] Moulton, H. M., M. H. Nelson, et al. (2004). "Cellular uptake of antisense morpholino oligomers conjugated to arginine-rich peptides." Bioconjug Chem 15(2): 290-9. [0019] Nelson, M. H., D. A. Stein, et al. (2005). "Arginine-rich peptide conjugation to morpholino oligomers: effects on antisense activity and specificity." Bioconjug Chem 16(4): 959-66. [0020] Strauss, J. H. and E. G. Strauss (2002). Viruses and Human Disease. San Diego, Academic Press. [0021] Summerton, J. and D. Weller (1997). "Morpholino antisense oligomers: design, preparation, and properties." Antisense Nucleic Acid Drug Dev 7(3): 187-95. [0022] Toulme, J. J., R. L. Tinevez, et al. (1996). "Targeting RNA structures by antisense oligonucleotides." Biochimie 78(7): 663-73. [0023] Williams, A. S., J. P. Camilleri, et al. (1996). "A single intra-articular injection of liposomally conjugated methotrexate suppresses joint inflammation in rat antigen-induced arthritis." Br J Rheumatol 35(8): 719-24. [0024] Wu, G. Y. and C. H. Wu (1987). "Receptor-mediated in vitro gene transformation by a soluble DNA carrier system." J Biol Chem 262(10): 4429-32. BACKGROUND OF THE INVENTION [0025] Influenza viruses have been a major cause of human mortality and morbidity throughout recorded history. Influenza A virus infection causes millions of cases of severe illness and as many as 500,000 deaths each year worldwide. Epidemics vary widely in severity but occur at regular intervals and always cause significant mortality and morbidity, most frequently in the elderly population. Although vaccines against matched influenza strains can prevent illness in 60-80% of healthy adults, the rate of protection is much lower in high-risk groups. Furthermore, vaccination does not provide protection against unexpected strains, such as the H5 and H7 avian influenza outbreaks in Hong Kong in 1997 and Europe and Southeast Asia in 2003 and 2004. Current anti-influenza drugs are limited in their capacity to provide protection and therapeutic effect (Cox and Subbarao 1999; Cox and Subbarao 2000). [0026] Influenza A is a segmented RNA virus of negative-polarity. Genome segments are replicated by a complex of 4 proteins: the 3 polymerase polypeptides (PA, PB1 and PB2) and NP (Nucleoprotein). The 5' and 3' terminal sequence regions of all 8 genome segments are highly conserved within a genotype (Strauss and Strauss 2002). [0027] Influenza A viruses can be subtyped according to the antigenic and genetic nature of their surface glycoproteins; 15 hemagglutinin (HA) and 9 neuraminidase (NA) subtypes have been identified to date. Viruses bearing all known HA and NA subtypes have been isolated from avian hosts, but only viruses of the H1N1 (1918), H2N2 (1957/58), and H3N2 (1968) subtypes have been associated with widespread epidemics in humans (Strauss and Strauss 2002). [0028] Since 1997, when H5N1 influenza virus was transmitted to humans and killed 6 of 18 infected persons, there have been multiple transmissions of avian influenza viruses to mammals. Either the whole virus is transmitted directly or gene segments from the avian influenza virus are acquired by mammalian strains. Widespread infections of poultry with H5N1 viruses in Asia have caused increasing concern that this subtype may achieve human-to-human spread and establish interspecies transmission. The species which different types of influenza viruses are able to infect are determined by different forms of the virus glycoproteins (HA, NA). This provides a considerable species barrier between birds and humans which is not easily overcome. Pigs, however, provide a "mixing pot"-able to be infected by both types of virus and thereby allowing the passage of avian viruses to humans. When an individual pig cell is co-infected with both avian and human influenza viruses, recombinant forms can emerge that carry an avian HA genotype but readily infect humans. Avian HA can infect pigs, but not humans. In pigs, during genome segment packaging, it is possible to create a virus with several Avian segments and Human HA and/or NA segments (Cox and Subbarao 2000). [0029] Influenza viruses infect humans and animals (e.g., pigs, birds, horses) and may cause acute respiratory disease. There have been numerous attempts to produce vaccines effective against influenza virus. None, however, have been completely successful, particularly on a long-term basis. This may be due, at least in part, to the segmented characteristic of the influenza virus genome, which makes it possible, through re-assortment of the segments, for numerous forms to exist. For example, it has been suggested that there could be an interchange of RNA segments between animal and human influenza viruses, which would result in the introduction of new antigenic subtypes into both populations. Thus, a long-term vaccination approach has failed, due to the emergence of new subtypes (antigenic "shift"). In addition, the surface proteins of the virus, hemagglutinin and neuraminidase, constantly undergo minor antigenic changes (antigenic "drift"). This high degree of variation explains why specific immunity developed against a particular influenza virus does not establish protection against new variants. Hence, alternative antiviral strategies are needed. Although influenza B and C viruses cause less clinical disease than the A types, new antiviral drugs should also be helpful in curbing infections caused by these agents. [0030] Influenza viruses that occur naturally among birds are called avian influenza (bird flu). The birds carry the viruses in their intestines but do not generally get sick from the infection. However, migratory birds can carry the bird flu to infect domestic chickens, ducks and turkeys causing illness and even death. Avian flu does not easily infect humans but when human exposure is more frequent, such as contact with domestic birds, human infections occur. A dangerous bird flu (H5N1) was first identified in terns in South Africa in 1961 and was identified as a potentially deadly form of flu. Outbreaks of H5N1 occurred in eight Asian countries in late 2003 and 2004. At that time more than 100 million birds in these countries either died or were killed in order to control the outbreak. Beginning in June of 2004 new deadly outbreaks of H5N1 were reported in Asia which is currently ongoing. Human infections of H5N1 have been observed in Thailand, Vietnam and Cambodia with a death rate of about 50 percent. These infections have mostly occurred from human contact with infected poultry but a few cases of human-to-human spread of H5N1 have occurred. [0031] Currently, there is no vaccine to protect humans against H5N1 but research efforts are underway. There are four currently approved influenza medications, amantadine, rimantadine, oseltamivir and zanamivir. Unfortunately, the H5N1 virus is resistant to both amantadine and rimantidine. The remaining oseltamivir and zanamivir may show some efficacy to H5N1 but need to be evaluated more extensively. [0032] In view of the severity of the diseases caused by influenza viruses there is an immediate need for new therapies to treat influenza infection. Given the lack of effective prevention or therapies, it is therefore an object of the present invention to provide therapeutic compounds and methods for treating a host infected with an influenza virus. SUMMARY OF THE INVENTION [0033] The invention includes, in one aspect, an anti-viral compound effective in inhibiting replication within a host cell of an RNA virus having a single-stranded, negative sense genome and selected from the Orthomyxoviridae family including the Influenzavirus A, Influenzavirus B and Influenzavirus C genera. The compound targets viral RNA sequences within a region selected from the following: 1) the 5' or 3' terminal 25 bases of the negative sense viral RNA segments; 2) the terminal 25 bases of the 3' terminus of the positive sense cRNA and; 3) 50 bases surrounding the AUG start codons of influenza viral mRNAs. [0034] The antiviral compound consists of an oligonucleotide analog characterized by: a) a nuclease-resistant backbone, b) 12-40 nucleotide bases, and c) a targeting sequence of at least 12 bases in length, that hybridizes to a target region selected from the following: i) the 5' or 3' terminal 25 bases of a negative sense viral RNA segment of Influenzavirus A, Influenzavirus B and Influenzavirus C, ii) the terminal 30 bases of the 3' terminus of a positive sense cRNA of Influenzavirus A, Influenzavirus B and Influenzavirus C, and iii) the 50 bases surrounding the AUG start codon of an influenza viral mRNA. [0035] The oligonucleotide analog also has: a) the capability of being actively taken up by mammalian host cells, and b) the ability to form a heteroduplex structure with the viral target region, wherein said heteroduplex structure is: i) composed of the positive or negative sense strand of the virus and the oligonucleotide compound, and ii) characterized by a Tm of dissociation of at least 45.degree. C. [0036] The invention includes, in another aspect, an antiviral compound that inhibits, in a mammalian host cell, replication of an infecting influenza virus having a single-stranded, segmented, negative-sense genome and selected from the Orthomyxoviridae family. The compound is administered to the infected host cells as an oligonucleotide analog characterized by the elements described above on pp. 5-6. The compound may be administered to a mammalian subject infected with the influenza virus, or at risk of infection with the influenza virus. [0037] The compound may be composed of morpholino subunits linked by uncharged, phosphorus-containing intersubunit linkages, joining a morpholino nitrogen of one subunit to a 5' exocyclic carbon of an adjacent subunit. In one embodiment, the intersubunit linkages are phosphorodiamidate linkages, such as those having the structure: where Y.sub.1.dbd.O, Z=O, Pj is a purine or pyrimidine base-pairing moiety effective to bind, by base-specific hydrogen bonding, to a base in a polynucleotide, and X is alkyl, alkoxy, thioalkoxy, or alkyl amino, e.g., wherein X.dbd.NR.sub.2, where each R is independently hydrogen or methyl. [0038] The compound may be composed of morpholino subunits linked with the uncharged linkages described above interspersed with linkages that are positively charged at physiological pH. The total number of positively charged linkages is between 2 and no more than half of the total number of linkages. The positively charged linkages have the structure above, where X is 1-piperazine. [0039] The compound may be a covalent conjugate of an oligonucleotide analog moiety capable of forming such a heteroduplex structure with the positive or negative sense strand of the virus, and an arginine-rich polypeptide effective to enhance the uptake of the compound into host cells. Exemplary polypeptides have one of the sequences identified as SEQ ID NOs:25-30. [0040] In a related aspect, the invention includes a heteroduplex complex formed between: [0041] (a) the 5' or 3' terminal 25 bases of the negative sense viral RNA and/or; [0042] (b) the terminal 25 bases of the 3' terminus of the positive sense mRNA and/or; [0043] (c) 50 bases surrounding the AUG start codons of viral mRNA of an influenza virus selected from the Orthomyxoviridae family and, [0044] (d) an oligonucleotide analog compound characterized by: [0045] (i) a nuclease-resistant backbone, [0046] (ii) capable of uptake by mammalian host cells, [0047] (iii) containing between 12-40 nucleotide bases, [0048] where said heteroduplex complex has a Tm of dissociation of at least 45.degree. C. and disruption of a stem-loop secondary structure. Continue reading about Antisense antiviral compound and method for treating influenza viral infection... 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