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(12) United States Patent (10) Patent No.: US 8,629,283 B2 Shaw Et Al USOO8629283B2 (12) United States Patent (10) Patent No.: US 8,629,283 B2 Shaw et al. (45) Date of Patent: Jan. 14, 2014 (54) COMPOUNDS THAT MODULATE Fabbri et al., 1994, “Export of protein from the endoplasmic NEGATIVE-SENSE, SINGLE-STRANDED RNA reticulum is regulated by a diacylglycerol/phorbol ester binding pro tein', J Biol Chem; 269(43):26848-26857. VIRUS REPLICATION AND USES THEREOF Gschwendt et al., 1994, "Rottlerin, a novel protein kinase inhibitor'. (75) Inventors: Megan L. Shaw, New York, NY (US); Biochem Biophys Res Commun; 199(1):93-98. Hans-Heinrich Hoffmann, New York, Guggino et al., 2000, “Amiloride-sensitive sodium channels contrib ute to the woes of the flu'. Proc Natl Acad Sci USA, 97(18):9827 NY (US); Adolfo Garcia-Sastre, New 98.29. York, NY (US); Peter Palese, New York, Iioffmann et al., 2008, “Modulation of influenza virus replication by NY (US) alteration of sodium ion transport and protein kinase C activity'. Dept.of Microbiology, Mount Sinai School of Medicine, New York, (73) Assignee: Icahn School of Medicine at Mount NY 10O29. Sinai, New York, NY (US) Hoffmann et al., 2008, “Modulation of influenza virus replication (*) Notice: Subject to any disclaimer, the term of this identified via a high-throughput screening approach'. Dept.of patent is extended or adjusted under 35 Microbiology, Mount Sinai School of Medicine, New York, NY U.S.C. 154(b) by 375 days. 10O29. International Search Report of International application No. PCT/ (21) Appl. No.: 12/921,077 US2009/00 1474, dated Jan. 18, 2010. (22) PCT Filed: Mar. 6, 2009 International Search Report of International application No. PCT/ US2011/38515, dated Sep. 13, 2011. (86). PCT No.: PCT/US2O09/OO1474 Kistner et al., 1989, “Differential phosphorylation of the nucleoprotein of influenza A viruses”. J Gen Virol; 70:2421-2431. S371 (c)(1), Kleyman et al., 1988, “Amiloride and its analogs as tools in the study (2), (4) Date: Dec. 13, 2010 of ion transport”. J. Membrane Biol; 105:1-21. U.S. Appl. No. 13/700,049, filed Nov. 26, 2012, Shaw. KunzelmAnn et al., 2000, "Influenza virus inhibits amiloride-sensi (87) PCT Pub. No.: WO2009/136979 tive Na"channels in respiratory epithelia'. Proc Natl AcadSci USA; PCT Pub. Date: Nov. 12, 2009 97(18): 10282-10287. Kurokawa et al., 1990, "Inhibitory effect of protein kinase Cinhibitor (65) Prior Publication Data on the replication of influenza type A virus', J Gen Virol; 71(Pt US 2011 FO105423 A1 May 5, 2011 9):2149-2155. Lee ct al., 2007, "Crystal structure of the VP4 protcasc from infc Related U.S. Application Data ctious pancreatic necrosis virus rcvcals the acylenzyme complex for an intermolecular self-cleavage reaction', J Biol Chem; (60) Provisional application No. 61/034,459, filed on Mar. 282(34):24928-24937. 6, 2008. Link et al., 1966, "Interaction of heart glycosides and viruses'. Acta Virol; 10:455-461. (51) Int. Cl. Mahmoudian et al., 2009, “Influenza A virus proteins PB1 and NS1 C07D 27L/I 13 (2006.01) are subject to functionally important phosphorylation by protein (52) U.S. Cl. kinase C, J Gen Virol; 90(Pt6): 1392-1397. CPC .................................. C07D 27I/I 13 (2013.01) Nagai et al., 1972, "Inhibition of virus growth by ouabain: effect of USPC .......................................................... 548/144 ouabain on the growth of HVJ in chick embryo cells”. J. Virol; (58) Field of Classification Search 9(2): 234-243. None Patterson et al., 1979, “Studies on the mechanism of influenza virus entry into cells”, J Gen Virol; 43(223-229). See application file for complete search history. Rootet al., 2000, “Entry of influenza viruses into cells is inhibited by a highly specific protein kinase C inhibitor'. J Gen Virol; 81 (Pt (56) References Cited 11):2697-2705. U.S. PATENT DOCUMENTS (Continued) 6,384,064 B2 5, 2002 Camden 8,278,342 B2 10/2012 Ricciardi Primary Examiner — Eric S Olson 2005/O123902 A1 6, 2005 Meneses et al. (74) Attorney, Agent, or Firm — Jones Day 2005/023.9906 A1 10/2005 Garaci et al. 2009,0162831 A1 6, 2009 Delwart et al. (57) ABSTRACT 2010.0035887 A1 2/2010 Ricciardi The present invention relates to compounds that modulate the FOREIGN PATENT DOCUMENTS replication of negative-sense, single-stranded RNA viruses, Such as influenza virus, and the use of such compounds. The WO WO 2011 150413 A1 12/2011 invention relates to methods for increasing the titer of nega tive-sense, single-stranded RNA viruses, such as influenza OTHER PUBLICATIONS virus, in Substrates for virus propagation (e.g., tissue culture). Hoffmann et al., “Broad-spectrum antiviral that interferes with de The invention also relates to the use of compounds that novo pyrimidine biosynthesis' PNAS (2011) vol. 108 No. 14 pp. decrease virus replication as antiviral agents. The invention 5777-5782.* further relates to methods for identifying compounds that Rigautet al., 1991, “Inhibition of VSV infection by staurosporine'. J modulate the replication of negative-sense, single-stranded Cell Biol; 115(3Part2):476A. RNA viruses, in particular, influenza virus. Cien et al., 2004. “Influenza A virus PB1-F2 gene in recent Taiwan ese isolates'. Emerging Infectious Diseases; 10(4): 630-635. 6 Claims, 13 Drawing Sheets US 8,629,283 B2 Page 2 (56) References Cited Sieczkarski et al., 2003, “Role of protein kinase C BII in influenza virus entry via late endosomes”, JVirol; 77(1):460-469. Wright et al., 2009, "Inhibition of simian virus 40 replication by OTHER PUBLICATIONS targeting the molecular chaperone function and ATPase activity of T antigen'. Virus Res; 141(1):71-80. Salvatore et al., 2007, "O-defensin inhibits influenza virus replication Written Opinion of International application No. PCT/US2009/ by cell-mediated mechanism(s)”, JID; 196:835-843. 00.1474, dated Jan. 18, 2010. Scholtissek et al., 1986, "Influence of insulin and 12-O- Written Opinion of International application No. PCT/US2011/ tetradecanoylphorbol-13-acetate (TPA) on influenza virus multipli 38515, dated Sep. 13, 2011. cation, Virus Res; 6:287-294. Yiet al., 2008, “A secondary gate as a mechanism for inhibition of the Shaw et al., 2008, “Opposing effects on influenza growth by com M2 proton channel by amantadine'. J. Phys Chem; 112(27):7977 pounds targeting both sodium channels and protein kinase C. Dept. 7979. of Microbiology, Mount Sinai School of Medicine, New York, NY 10029 (Abstract only). * cited by examiner U.S. Patent US 8,629,283 B2 U.S. Patent Jan. 14, 2014 Sheet 2 of 13 US 8,629,283 B2 s (uff '60) Jel) e IA C AqelAa3 "y, U (LLuffo) a leA U.S. Patent Jan. 14, 2014 Sheet 4 of 13 US 8,629,283 B2 A Inhibition of influenza A/WSN/33 virus 7 untreated 12.5uM 1.25uM Control SDZ-2011 O6 rOtterin B Inhibition of influenza B/Yamagata/88 virus 6 Untreated 12.5uM 1.25uM Control SDZ-201106 rottlerin Fig. 4 U.S. Patent Jan. 14, 2014 Sheet 5 of 13 US 8,629,283 B2 A Enhancement of influenza A virus by Na-channel inhibitors 9 mom 2',4'-dichlorobenzami- 400nM . .0 . phenamil 1 OuM 8 re- Alce untreated Control S R 7 n g 6 s 5 / is ... s 4. < 3 - O 24 36 48 60 hours post infection B Enhancement of influenza A virus by PKC activators 9 -0- mezerein 25OnM rare PMA 250nM 8 tries untreated Control 6 O 24 36 48 6O hours post infection Fig. 5 U.S. Patent Jan. 14, 2014 Sheet 6 of 13 US 8,629,283 B2 Enhancement of influenza B/Yamagata/88 virus 7 sm mezerein 250nM -0m- 2',4'-dichlorobenzamil 400nM serie untreated Control O 12 24 36 48 hours post infection Fig. 6 U.S. Patent Jan. 14, 2014 Sheet 7 of 13 US 8,629,283 B2 09 8798#7 0 (Uu/n fo) ue eum U.S. Patent Jan. 14, 2014 Sheet 8 of 13 US 8,629,283 B2 Enhancement of influenza A virus by amiloride derivatives 10 E 9 2 3. 8 s s 7 untreated 2',4'- 3',4'- control dichlorobenzamil dichlorobenzami Fig. 8 U.S. Patent Jan. 14, 2014 Sheet 9 of 13 US 8,629,283 B2 A A549 cells infected with influenza A/WSN/33 virus in the presence of 12.5uM SDZ-201106 (24hpi) 8 S S 7 e s 6 WSN- WSN + SDZ- WSN (P15) - WSN (P15) untreated 2O1105 untreated SD7-201106 Student's t test: *, Ps. O.O. B A549 cells infected with influenza A/WSN/33 virus in the presence of 1.25M rottlerin (24hpi) 1E+7 O 1E-6 s WSN (wt) - WSN (wt) + (WSN (P17) - WSN (P17) untreated rottlerin untreated rottlerin Student's t test: , PS 0.05 Fig. 9 U.S. Patent Jan. 14, 2014 Sheet 10 of 13 US 8,629,283 B2 1. E s 7 1. E H 6 1E-5 untreated 2hprior inf. 1 hpi 2hpi 4hpi compound added Fig. 10 1E+4 -2 1. 2 4. 6 8 12 24 start of compound treatment in hours post infection Fig.11 U.S. Patent Jan. 14, 2014 Sheet 11 of 13 US 8,629,283 B2 1 E-8 1. E 7 1 E-6 untreated 2h prior inf. 1 hpi compound added Fig. 12 1-E--8 1.E-7 1. E-6 1. E-5 1. E-4 1-E-3 untreated A3 A35 untreated C2 control control Fig. 13 U.S. Patent Jan. 14, 2014 Sheet 12 of 13 US 8,629,283 B2 A 1.E--7 E-6 1. E-5 E-4 1. E-3 1. E-2 untreated A3 A35 untreated C2 control control 1.
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