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(12) Patent Application Publication (10) Pub. No.: US 2006/0063150 A1 Iversen Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2006/0063150 A1 Iversen Et Al US 2006OO63150A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/0063150 A1 Iversen et al. (43) Pub. Date: Mar. 23, 2006 (54) ANTISENSE ANTIVIRAL COMPOUND AND Publication Classification METHOD FOR TREATING SSRNA WRAL INFECTION (51) Int. Cl. CI2O 1/70 (2006.01) G06F I9/00 (2006.01) (76) Inventors: Patrick L. Iversen, Corvallis, OR CI2P 1934 (2006.01) A6IK 4800 (2006.01) (US); David A. Stein, Corvallis, OR (52) U.S. Cl. ................ 435/5; 435/912; 514/44; 702/20; (US) 514/81 Correspondence Address: (57) ABSTRACT PERKINS COE LLP The invention provides antisense antiviral compounds and P.O. BOX 21.68 methods of their use and production in inhibition of growth MENLO PARK, CA 94026 (US) of viruses of the Flaviviridae, Picornoviridae, Caliciviridae, Togaviridae, Arteriviridae, Coronaviridae, Astroviridae and (21) Appl. No.: 11/226,995 Hepeviridae families in the treatment of a viral infection. The antisense antiviral compounds are Substantially (22) Filed: Sep. 14, 2005 uncharged morpholino oligonucleotides having a Sequence of 12-40 Subunits, including at least 12 Subunits having a Related U.S. Application Data targeting Sequence that is complementary to a region asso ciated with Stem-loop Secondary Structure within the 5'-ter (60) Provisional application No. 60/611,063, filed on Sep. minal end 40 bases of the positive-sense RNA strand of the 16, 2004. WUS. Patent Application Publication Mar. 23, 2006 Sheet 1 of 12 US 2006/0063150 A1 ', , R Y- B O - O, 9 p CH2 m so O=P-R C=O m 's- 7B O NH O o O Fig. 1A Fig. 1B Fig. 1C "loO O loO B m R. S O=s=O CH2 R 1. O B o O- B R. Ó CH3. O=P-N, CH3 B N Patent Application Publication Mar. 23, 2006 Sheet 2 of 12 US 2006/0063150 A1 z- 'O =-x ' { P N Fig. 2A Fig. 2B N N ZP-X ) y Z-P-X Y ''' ": N N Patent Application Publication Mar. 23, 2006 Sheet 3 of 12 US 2006/006.3150 A1 Legend:stigiitigategiztigatzigzag HRV89 polyprotein rt ...t-r-t CBS.S., in - no w Fig. 3A- rt Trrrrrrrrrrrrrt 7654 EenOnstructural58kd capsid pre-2EEE polyprotein yp Legend: Orf3s cera - CDS cea - gene r"T" -1000-2000. Fig d 3B 1mm - "9755 assessessessessite nonstructural pO E" Legend: mRNA-Subgenomic RNA.ii. cra - CDS m - RNA tra - gene Trrrrtm - 1000-2000, Fig. 3C 6 EE , -- polyprotein Legend:repeat region - repeat region" reca - CDS as - gene arms - other feature TTTTTTTT - 1000-2000. Fig. 3D SCII 2737 Corries rececareplicase polyprotein areplicase Picas FIRpolyprotein 1ab an Patent Application Publication Mar. 23, 2006 Sheet 5 of 12 US 2006/0063150 A1 Patent Application Publication Mar. 23, 2006 Sheet 6 of 12 US 2006/0063150 A1 8 -Q &c. Patent Application Publication Mar. 23, 2006 Sheet 8 of 12 US 2006/0063150 A1 Patent Application Publication Mar. 23, 2006 Sheet 9 of 12 US 2006/0063150 A1 uoneo||des|-Naquo Z unjd Olfo 4034434oT.S.G.OWdDHS)QI(?g:ONuo Patent Application Publication Mar. 23, 2006 Sheet 10 of 12 US 2006/0063150 A1 E&::::::::: 34s &xisS& Patent Application Publication Mar. 23, 2006 Sheet 11 of 12 US 2006/0063150 A1 601 Patent Application Publication Mar. 23, 2006 Sheet 12 of 12 US 2006/0063150 A1 3 S S. C O (VS .9 s Y i le). Oulu.OO pejeanun % Hs ./ O O O e s N N O p N in O O 2. 2 O d Se a. go- assessessr asses L?) CO Je). Oluod peee Jun / US 2006/OO63150 A1 Mar. 23, 2006 ANTISENSE ANTIVIRAL COMPOUND AND 0014) Moulton, H. M., M. H. Nelson, et al. (2004). METHOD FOR TREATING SSRNA WRAL “Cellular uptake of antisense morpholino oligomers con INFECTION jugated to arginine-rich peptides. Bioconjug Chem 15(2): 0001. This application claims priority to U.S. provisional 290-9. patent application No. 60/611,063 filed on Sep. 16, 2004, 0.015 Murray, R. and e. al. (1998). Medical Microbiol which is incorporated herein in its entirety by reference. ogy. St. Louis, Mo., Mosby Press: 542-543. FIELD OF THE INVENTION 0016) Neuman, B. W., D. A. Stein, et al. (2004). “Anti sense Morpholino-Oligomers Directed against the 5' End 0002 This invention relates to antisense oligonucleotide of the Genome Inhibit Coronavirus Proliferation and compounds for use in treating a Flavivirus, Hepacivirus, Growth dagger.' J. Virol. 78(11): 5891-5899. Enterovirus, Rhinovirus, Hepatovirus, Apthovirus, Hepevi rus, Coronavirus, Arterivirus, Vesivirus, Norovirus, 0017 O'Ryan, M. (1992). Clinical Virology Manual. S. Mamastrovirus, Alphavirus, and Rubivirus infection and Spector and G. Lancz. New York, Elsevier Science: antiviral treatment methods employing the compounds. 361-196. 0.018 Pardigon, N., E. Lenches, et al. (1993). “Multiple REFERENCES binding sites for cellular proteins in the 3' end of Sindbis 0003. The following references are related to the back alphavirus minus-sense RNA.'J Virol 67(8): 5003-11. ground or the invention. 0.019 Pardigon, N. and J. H. Strauss (1992). “Cellular 0004 Banerjee, R. and A. Dasgupta (2001). “Interaction proteins bind to the 3' end of Sindbis virus minus-strand of picornavirus 2C polypeptide with the Viral negative RNA. J Virol 66(2): 1007-15. strand RNA. J Gen Virol 82(Pt. 11): 2621-7. 0020 Paul, A. V. (2002). Possible unifying mechanism of 0005 Banerjee, R. and A. Dasgupta (2001). “Specific picornavirus genome replication. Molecular Biology of interaction of hepatitis C virus protease/helicase NS3 with Picornaviruses. B. L. Semler and E. Wimmer. Washing the 3'-terminal Sequences of Viral positive- and negative ton, D.C., ASM Press: 227-246. strand RNA. J Virol 75(4): 1708-21. 0021) Roehl, H. H., T. B. Parsley, et al. (1997). “Process 0006 Banerjee, R., A. Echeverri, et al. (1997). “Poliovi ing of a cellular polypeptide by 3CD proteinase is rus-encoded 2C polypeptide specifically binds to the required for poliovirus ribonucleoprotein complex forma 3'-terminal sequences of viral negative-strand RNA.J tion.”J Virol 71(1): 578-85. Virol 71(12): 9570-8. 0022 Roehl, H. H. and B. L. Semler (1995). “Poliovirus 0007 Banerjee, R., W. Tsai, et al. (2001). “Interaction of infection enhances the formation of two ribonucleopro poliovirus-encoded 2C/2BC polypeptides with the 3' ter tein complexes at the 3' end of Viral negative-Strand minus negative-Strand cloverleaf requires an intact Stem RNA. J Virol 69(5): 2954-61. loop b.”Virology 280(1): 41-51. 0023 Smith, A. W., D. E. Skilling, et al. (1998). “Cali 0008 Blommers, M. J., U. Pieles, et al. (1994). “An civirus emergence from Ocean reservoirs: Zoonotic and approach to the Structure determination of nucleic acid interspecies movements.” Emerg Infect Dis 4(1): 13-20. analogues hybridized to RNA. NMR studies of a duplex between 2'-OMe RNA and an oligonucleotide containing 0024 Summerton, J. and D. Weller (1997). “Morpholino a single amide backbone modification.'Nucleic Acids Res antisense oligomers: design, preparation, and properties 22(20): 4187-94. .'Antisense Nucleic Acid Drug Dev 7(3): 187-95. 0009 Gait, M. J., A. S. Jones, et al. (1974). “Synthetic 0.025 Xu, W.Y. (1991). “Viral haemorrhagic disease of analogues of polynucleotides XII. Synthesis of thymidine rabbits in the People's Republic of China: epidemiology derivatives containing an oxyacetamido- or an oxyforma and virus characterisation.'Rev Sci Tech 10(2): 393-408. mido-linkage instead of a phosphodiester group.'J Chem 0026. Zuker, M. (2003). “Mfold web server for nucleic Soc Perkin 10(14): 1684-6. acid folding and hybridization prediction.” Nucleic Acids 0010 Holland, J. (1993). Emerging Virus. S. S. Morse. Res 31(13): 3406-15. New York and Oxford, Oxford University Press: 203-218. BACKGROUND OF THE INVENTION 0011 Lesnikowski, Z. J., M. Jaworska, et al. (1990). "Octa(thymidine methanephosphonates) of partially 0027 Single-stranded RNA (ssRNA) viruses cause many defined stereochemistry: synthesis and effect of chirality diseases in wildlife, domestic animals and humans. These at phosphorus on binding to pentadecadeoxyriboadenylic Viruses are genetically and antigenically diverse, exhibiting broad tissue tropisms and a wide pathogenic potential. The acid."Nucleic Acids Res 18(8): 2109-15. incubation periods of Some of the most pathogenic viruses, 0012 Markoff, L. (2003). “5’- and 3'-noncoding regions e.g. the caliciviruses, are very short. Viral replication and in flavivirus RNA.A.d Virus Res 59: 177-228. expression of virulence factors may overwhelm early 0013 Mertes, M. P. and E. A. Coats (1969). “Synthesis of defense mechanisms (Xu 1991) and cause acute and severe carbonate analogs of dinucleosides. 3'-Thymidinyl 5'-thy Symptoms. midinyl carbonate, 3'-thymidinyl 5'-(5-fluoro-2'-deox 0028. There are no specific treatment regimes for many yuridinyl) carbonate, and 3'-(5-fluoro-2'-deoxyuridinyl) Viral infections. The infection may be Serotype specific and 5'-thymidinyl carbonate.”J Med Chem 12(1): 154-7. natural immunity is often brief or absent (Murray and al. US 2006/OO63150 A1 Mar. 23, 2006 1998). Immunization against these virulent viruses is 0038 (i) a nuclease-resistant backbone, impractical because of the diverse Serotypes. RNA virus replicative processes lack effective genetic repair mecha 0039 (ii) capable of uptake by mammalian host cells, nisms, and current estimates of RNA virus replicative error 0040 (iii) containing between 12-40 nucleotide bases, rates are Such that each genomic replication can be expected and to produce one to ten errors, thus generating a high number 0041 (iv) having a targeting Sequence of at least 12 of variants (Holland 1993). Often, the serotypes show no Subunits that is complementary to a region within the croSS protection Such that infection with any one Serotype 5'-terminal 40 bases of the positive-strand viral genome that does not protect against infection with another.
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