Structure-Based Discovery of Novel Cyclophilin A Inhibitors for the Treatment of Hepatitis C Virus Infections

Journal of Medicinal Chemistry

Volumn 58, Issue 24, 2015, Pages 9546-9561

  Yang, Suhui ^a,f   Jyothi, K R ^b   Lim, Sangbin ^b   Choi, Tae Gyu ^b   Kim, Jin Hwan ^b   Akter, Salima ^b   Jang, Miran ^b   Ahn, Hyun Jong ^b   Kim, Hee Young ^c   Windisch, Marc P ^c   Khadka, Daulat B ^a   Zhao, Chao ^a   Jin, Yifeng ^a   Kang, Insug ^b   Ha, Joohun ^b   Oh, Byung Chul ^d   Kim, Meehyein ^e   Kim, Sung Soo ^b   Cho, Won Jea ^a  

^a Chonnam National University   (South Korea)

^b Kyung Hee University Hospital   (South Korea)

^c Institute Pasteur Korea   (South Korea)

^d Gachon University College of Medicine   (South Korea)

^e Korea Research Institute of Chemical Technology   (South Korea)

^f UNIVERSITY OF MICHIGAN   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ACETAMIDE DERIVATIVE; ALISPORIVIR; ALPHA INTERFERON; AMIDE; ANTIVIRUS AGENT; CYCLOPHILIN A; CYCLOPHILIN A INHIBITOR; CYCLOPHILIN INHIBITOR; CYCLOSPORIN A; CYCLOSPORIN A [4 N METHYLISOLEUCINE]; N CYCLOHEXYL 2 [( 2 1H INDOL 3 YLACETYL)( 4 ISOPROPYLPHENYL)AMNO] 2 ( 3,4,5 TRIMETHOXYPHENYL)ACETAMIDE; RIBAVIRIN; SCY 635; TELAPREVIR; UNCLASSIFIED DRUG; GLYCINE; INDOLEACETIC ACID DERIVATIVE; N-CYCLOHEXYL-2-((2-1H-INDOL-3-YLACETYL)-(4-ISOPROPYLPHENYL)AMINO)-2-(3,4,5-TRIMETHOXYPHENYL)ACETAMIDE; PROTEIN BINDING;

ACUTE TOXICITY; ANIMAL EXPERIMENT; ANIMAL TISSUE; ANTIVIRAL ACTIVITY; ARTICLE; CELL LINE; CONTROLLED STUDY; CYTOTOXICITY; DRUG DESIGN; DRUG EFFECT; DRUG POTENCY; DRUG PROTEIN BINDING; DRUG SCREENING; DRUG SYNTHESIS; FEMALE; HEPATITIS C; HEPATITIS C VIRUS; HUMAN; HUMAN CELL; IC50; IN VITRO STUDY; IN VIVO STUDY; MOLECULAR MODEL; MOUSE; NONHUMAN; STRUCTURE ACTIVITY RELATION; VIRUS IMMUNITY; VIRUS REPLICATION; VIRUS STRAIN; ANALOGS AND DERIVATIVES; ANIMAL; ANTAGONISTS AND INHIBITORS; CHEMICAL STRUCTURE; CHEMISTRY; DRUG EFFECTS; DRUG POTENTIATION; HEPACIVIRUS; IMMUNOLOGY; IMMUNOSUPPRESSIVE TREATMENT; NONOBESE DIABETIC MOUSE; PHYSIOLOGY; REPLICON; SCID MOUSE; TUMOR CELL LINE; VIROLOGY;

ANIMALS; ANTIVIRAL AGENTS; CELL LINE, TUMOR; CYCLOPHILIN A; DRUG SYNERGISM; GLYCINE; HEPACIVIRUS; HEPATITIS C; HUMANS; IMMUNOSUPPRESSION; INDOLEACETIC ACIDS; MICE, INBRED NOD; MICE, SCID; MODELS, MOLECULAR; PROTEIN BINDING; REPLICON; STRUCTURE-ACTIVITY RELATIONSHIP; VIRUS REPLICATION;

EID: 84953268731     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/acs.jmedchem.5b01064     Document Type: Article

References (49)

1. Seeff, L. B. Natural history of hepatitis C Hepatology 1997, 26, 21S-28S 10.1002/hep.510260704
2. Kowdley, K. V. Hematologic side effects of interferon and ribavirin therapy J. Clin. Gastroenterol. 2005, 39, S3-8 10.1097/01.mcg.0000145494.76305.11
3. Strader, D. B.; Seeff, L. B. A brief history of the treatment of viral hepatitis C Clin. Liver Dis. 2012, 1, 6-11 10.1002/cld.1
4. Heim, M. H. 25 years of interferon-based treatment of chronic hepatitis C: an epoch coming to an end Nat. Rev. Immunol. 2013, 13, 535-542 10.1038/nri3463
5. Liang, T. J.; Ghany, M. G. Current and future therapies for hepatitis C virus infection N. Engl. J. Med. 2013, 368, 1907-1917 10.1056/NEJMra1213651
6. Manns, M. P.; von Hahn, T. Novel therapies for hepatitis C-one pill fits all? Nat. Rev. Drug Discovery 2013, 12, 595-610 10.1038/nrd4050
7. Sherman, K. E.; Flamm, S. L.; Afdhal, N. H.; Nelson, D. R.; Sulkowski, M. S.; Everson, G. T.; Fried, M. W.; Adler, M.; Reesink, H. W.; Martin, M.; Sankoh, A. J.; Adda, N.; Kauffman, R. S.; George, S.; Wright, C. I.; Poordad, F. Response-guided telaprevir combination treatment for hepatitis C virus infection N. Engl. J. Med. 2011, 365, 1014-1024 10.1056/NEJMoa1014463
8. Bacon, B. R.; Gordon, S. C.; Lawitz, E.; Marcellin, P.; Vierling, J. M.; Zeuzem, S.; Poordad, F.; Goodman, Z. D.; Sings, H. L.; Boparai, N.; Burroughs, M.; Brass, C. A.; Albrecht, J. K.; Esteban, R. Boceprevir for previously treated chronic HCV genotype 1 infection N. Engl. J. Med. 2011, 364, 1207-1217 10.1056/NEJMoa1009482
9. Yau, A. H.; Yoshida, E. M. Hepatitis C drugs: the end of the pegylated interferon era and the emergence of all-oral interferon-free antiviral regimens: a concise review Can. J. Gastroenterol. Hepatol. 2014, 28, 445-451
10. Wyles, D.; Pockros, P.; Morelli, G.; Younes, Z.; Svarovskaia, E.; Yang, J. C.; Pang, P. S.; Zhu, Y.; McHutchison, J. G.; Flamm, S.; Lawitz, E. Ledipasvir-sofosbuvir plus ribavirin for patients with genotype 1 hepatitis C virus previously treated in clinical trials of sofosbuvir regimens Hepatology 2015, 61, 1793-1797 10.1002/hep.27814
11. Lalezari, J.; Sullivan, J. G.; Varunok, P.; Galen, E.; Kowdley, K. V.; Rustgi, V.; Aguilar, H.; Felizarta, F.; McGovern, B.; King, M.; Polepally, A. R.; Cohen, D. E. Ombitasvir/paritaprevir/r and dasabuvir plus ribavirin in HCV genotype 1-infected patients on methadone or buprenorphine J. Hepatol. 2015, 63, 364-369 10.1016/j.jhep.2015.03.029
12. Chayama, K.; Notsumata, K.; Kurosaki, M.; Sato, K.; Rodrigues, L., Jr.; Setze, C.; Badri, P.; Pilot-Matias, T.; Vilchez, R. A.; Kumada, H. Randomized trial of interferon- and ribavirin-free ombitasvir/paritaprevir/ritonavir in treatment-experienced hepatitis C virus-infected patients Hepatology 2015, 61, 1523-1532 10.1002/hep.27705
13. Jacobson, I. M.; Gordon, S. C.; Kowdley, K. V.; Yoshida, E. M.; Rodriguez-Torres, M.; Sulkowski, M. S.; Shiffman, M. L.; Lawitz, E.; Everson, G.; Bennett, M.; Schiff, E.; Al-Assi, M. T.; Subramanian, G. M.; An, D.; Lin, M.; McNally, J.; Brainard, D.; Symonds, W. T.; McHutchison, J. G.; Patel, K.; Feld, J.; Pianko, S.; Nelson, D. R. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options N. Engl. J. Med. 2013, 368, 1867-1877 10.1056/NEJMoa1214854
14. Nelson, D. R.; Cooper, J. N.; Lalezari, J. P.; Lawitz, E.; Pockros, P. J.; Gitlin, N.; Freilich, B. F.; Younes, Z. H.; Harlan, W.; Ghalib, R.; Oguchi, G.; Thuluvath, P. J.; Ortiz-Lasanta, G.; Rabinovitz, M.; Bernstein, D.; Bennett, M.; Hawkins, T.; Ravendhran, N.; Sheikh, A. M.; Varunok, P.; Kowdley, K. V.; Hennicken, D.; McPhee, F.; Rana, K.; Hughes, E. A. All-oral 12-week treatment with daclatasvir plus sofosbuvir in patients with hepatitis C virus genotype 3 infection: ALLY-3 phase III study Hepatology 2015, 61, 1127-1135 10.1002/hep.27726
15. Ruane, P. J.; Ain, D.; Stryker, R.; Meshrekey, R.; Soliman, M.; Wolfe, P. R.; Riad, J.; Mikhail, S.; Kersey, K.; Jiang, D.; Massetto, B.; Doehle, B.; Kirby, B. J.; Knox, S. J.; McHutchison, J. G.; Symonds, W. T. Sofosbuvir plus ribavirin for the treatment of chronic genotype 4 hepatitis C virus infection in patients of Egyptian ancestry J. Hepatol. 2015, 62, 1040-1046 10.1016/j.jhep.2014.10.044
16. European Association for the Study of Liver. EASL Recommendations on Treatment of Hepatitis C 2015 J. Hepatol. 2015, 63, 199-236 10.1016/j.jhep.2015.03.025
17. Poveda, E.; Wyles, D. L.; Mena, A.; Pedreira, J. D.; Castro-Iglesias, A.; Cachay, E. Update on hepatitis C virus resistance to direct-acting antiviral agents Antiviral Res. 2014, 108, 181-191 10.1016/j.antiviral.2014.05.015
18. Wyles, D. L. Beyond telaprevir and boceprevir: resistance and new agents for hepatitis C virus infection Top. Antiviral Med. 2012, 20, 139-145
19. Pawlotsky, J. M. Treatment failure and resistance with direct-acting antiviral drugs against hepatitis C virus Hepatology 2011, 53, 1742-1751 10.1002/hep.24262
20. Xiao, F.; Fofana, I.; Heydmann, L.; Barth, H.; Soulier, E.; Habersetzer, F.; Doffoel, M.; Bukh, J.; Patel, A. H.; Zeisel, M. B.; Baumert, T. F. Hepatitis C virus cell-cell transmission and resistance to direct-acting antiviral agents PLoS Pathog. 2014, 10, e1004128 10.1371/journal.ppat.1004128
21. Aissa Larousse, J.; Trimoulet, P.; Recordon Pinson, P.; Tauzin, B.; Azzouz, M. M.; Ben Mami, N.; Cheikh, I.; Triki, H.; Fleury, H. Prevalence of hepatitis C virus (HCV) variants resistant to NS5A inhibitors in naive patients infected with HCV genotype 1 in Tunisia Virol. J. 2015, 12, 84 10.1186/s12985-015-0318-0
22. Tong, X.; Le Pogam, S.; Li, L.; Haines, K.; Piso, K.; Baronas, V.; Yan, J. M.; So, S. S.; Klumpp, K.; Najera, I. In vivo emergence of a novel mutant L159F/L320F in the NS5B polymerase confers low-level resistance to the HCV polymerase inhibitors mericitabine and sofosbuvir J. Infect. Dis. 2014, 209, 668-675 10.1093/infdis/jit562
23. Shi, N.; Hiraga, N.; Imamura, M.; Hayes, C. N.; Zhang, Y.; Kosaka, K.; Okazaki, A.; Murakami, E.; Tsuge, M.; Abe, H.; Aikata, H.; Takahashi, S.; Ochi, H.; Tateno-Mukaidani, C.; Yoshizato, K.; Matsui, H.; Kanai, A.; Inaba, T.; McPhee, F.; Gao, M.; Chayama, K. Combination therapies with NS5A, NS3 and NS5B inhibitors on different genotypes of hepatitis C virus in human hepatocyte chimeric mice Gut 2013, 62, 1055-1061 10.1136/gutjnl-2012-302600
24. Watashi, K.; Hijikata, M.; Hosaka, M.; Yamaji, M.; Shimotohno, K. Cyclosporin A suppresses replication of hepatitis C virus genome in cultured hepatocytes Hepatology 2003, 38, 1282-1288 10.1053/jhep.2003.50449
25. Chatterji, U.; Bobardt, M.; Selvarajah, S.; Yang, F.; Tang, H.; Sakamoto, N.; Vuagniaux, G.; Parkinson, T.; Gallay, P. The isomerase active site of cyclophilin A is critical for hepatitis C virus replication J. Biol. Chem. 2009, 284, 16998-17005 10.1074/jbc.M109.007625
26. Kaul, A.; Stauffer, S.; Berger, C.; Pertel, T.; Schmitt, J.; Kallis, S.; Zayas, M.; Lohmann, V.; Luban, J.; Bartenschlager, R. Essential role of cyclophilin A for hepatitis C virus replication and virus production and possible link to polyprotein cleavage kinetics PLoS Pathog. 2009, 5, e1000546 10.1371/journal.ppat.1000546
27. Liu, J. O. Calmodulin-dependent phosphatase, kinases, and transcriptional corepressors involved in T-cell activation Immunol. Rev. 2009, 228, 184-198 10.1111/j.1600-065X.2008.00756.x
28. Goto, K.; Watashi, K.; Murata, T.; Hishiki, T.; Hijikata, M.; Shimotohno, K. Evaluation of the anti-hepatitis C virus effects of cyclophilin inhibitors, cyclosporin A, and NIM811 Biochem. Biophys. Res. Commun. 2006, 343, 879-884 10.1016/j.bbrc.2006.03.059
29. Hopkins, S.; Scorneaux, B.; Huang, Z.; Murray, M. G.; Wring, S.; Smitley, C.; Harris, R.; Erdmann, F.; Fischer, G.; Ribeill, Y. SCY-635, a novel nonimmunosuppressive analog of cyclosporine that exhibits potent inhibition of hepatitis C virus RNA replication in vitro Antimicrob. Agents Chemother. 2010, 54, 660-672 10.1128/AAC.00660-09
30. Paeshuyse, J.; Kaul, A.; De Clercq, E.; Rosenwirth, B.; Dumont, J. M.; Scalfaro, P.; Bartenschlager, R.; Neyts, J. The non-immunosuppressive cyclosporin DEBIO-025 is a potent inhibitor of hepatitis C virus replication in vitro Hepatology 2006, 43, 761-770 10.1002/hep.21102
31. Zydowsky, L. D.; Etzkorn, F. A.; Chang, H. Y.; Ferguson, S. B.; Stolz, L. A.; Ho, S. I.; Walsh, C. T. Active site mutants of human cyclophilin A separate peptidyl-prolyl isomerase activity from cyclosporin A binding and calcineurin inhibition Protein Sci. 1992, 1, 1092-1099 10.1002/pro.5560010903
32. Davis, T. L.; Walker, J. R.; Campagna-Slater, V.; Finerty, P. J.; Paramanathan, R.; Bernstein, G.; MacKenzie, F.; Tempel, W.; Ouyang, H.; Lee, W. H.; Eisenmesser, E. Z.; Dhe-Paganon, S. Structural and biochemical characterization of the human cyclophilin family of peptidyl-prolyl isomerases PLoS Biol. 2010, 8, e1000439 10.1371/journal.pbio.1000439
33. Mikol, V.; Kallen, J.; Pflugl, G.; Walkinshaw, M. D. X-ray structure of a monomeric cyclophilin A-cyclosporin A crystal complex at 2.1 A resolution J. Mol. Biol. 1993, 234, 1119-1130 10.1006/jmbi.1993.1664
34. Ngouansavanh, T.; Zhu, J. Alcohols in isonitrile-based multicomponent reaction: Passerini reaction of alcohols in the presence of o-iodoxybenzoic acid Angew. Chem., Int. Ed. 2006, 45, 3495-3497 10.1002/anie.200600588
35. Domling, A. Recent developments in isocyanide based multicomponent reactions in applied chemistry Chem. Rev. 2006, 106, 17-89 10.1021/cr0505728
36. Borawski, J.; Troke, P.; Puyang, X.; Gibaja, V.; Zhao, S.; Mickanin, C.; Leighton-Davies, J.; Wilson, C. J.; Myer, V.; Cornellataracido, I.; Baryza, J.; Tallarico, J.; Joberty, G.; Bantscheff, M.; Schirle, M.; Bouwmeester, T.; Mathy, J. E.; Lin, K.; Compton, T.; Labow, M.; Wiedmann, B.; Gaither, L. A. Class III phosphatidylinositol 4-kinase alpha and beta are novel host factor regulators of hepatitis C virus replication J. Virol. 2009, 83, 10058-10074 10.1128/JVI.02418-08
37. Wu, Y.; Liao, Q.; Yang, R.; Chen, X. A novel luciferase and GFP dual reporter virus for rapid and convenient evaluation of hepatitis C virus replication Virus Res. 2011, 155, 406-414 10.1016/j.virusres.2010.11.009
38. Jang, Y. J.; Achary, R.; Lee, H. W.; Lee, H. J.; Lee, C. K.; Han, S. B.; Jung, Y. S.; Kang, N. S.; Kim, P.; Kim, M. Synthesis and anti-influenza virus activity of 4-oxo- or thioxo-4,5-dihydrofuro[3,4-c]pyridin-3(1H)-ones Antiviral Res. 2014, 107, 66-75 10.1016/j.antiviral.2014.04.013
39. Kim, O. H.; Kim, Y. O.; Shim, J. H.; Jung, Y. S.; Jung, W. J.; Choi, W. C.; Lee, H.; Lee, S. J.; Kim, K. K.; Auh, J. H.; Kim, H.; Kim, J. W.; Oh, T. K.; Oh, B. C. beta-propeller phytase hydrolyzes insoluble Ca(2+)-phytate salts and completely abrogates the ability of phytate to chelate metal ions Biochemistry 2010, 49, 10216-10227 10.1021/bi1010249
40. Chow, C. W.; Rincon, M.; Davis, R. J. Requirement for transcription factor NFAT in interleukin-2 expression Mol. Cell. Biol. 1999, 19, 2300-2307 10.1128/MCB.19.3.2300
41. Hopkins, S.; Gallay, P. Cyclophilin inhibitors: an emerging class of therapeutics for the treatment of chronic hepatitis C infection Viruses 2012, 4, 2558-2577 10.3390/v4112558
42. Kaufmann, Y.; Chang, A. E.; Robb, R. J.; Rosenberg, S. A. Mechanism of action of cyclosporin A: inhibition of lymphokine secretion studied with antigen-stimulated T cell hybridomas J. Immunol. 1984, 133, 3107-3111
43. Hopkins, S.; Bobardt, M.; Chatterji, U.; Garcia-Rivera, J. A.; Lim, P.; Gallay, P. A. The cyclophilin inhibitor SCY-635 disrupts hepatitis C virus NS5A-cyclophilin A complexes Antimicrob. Agents Chemother. 2012, 56, 3888-3897 10.1128/AAC.00693-12
44. Foster, T. L.; Gallay, P.; Stonehouse, N. J.; Harris, M. Cyclophilin A interacts with domain II of hepatitis C virus NS5A and stimulates RNA binding in an isomerase-dependent manner J. Virol. 2011, 85, 7460-7464 10.1128/JVI.00393-11
45. Blight, K. J.; Kolykhalov, A. A.; Rice, C. M. Efficient initiation of HCV RNA replication in cell culture Science 2000, 290, 1972-1974 10.1126/science.290.5498.1972
46. Kumthip, K.; Chusri, P.; Jilg, N.; Zhao, L.; Fusco, D. N.; Zhao, H.; Goto, K.; Cheng, D.; Schaefer, E. A.; Zhang, L.; Pantip, C.; Thongsawat, S.; O'Brien, A.; Peng, L. F.; Maneekarn, N.; Chung, R. T.; Lin, W. Hepatitis C virus NS5A disrupts STAT1 phosphorylation and suppresses type I interferon signaling J. Virol. 2012, 86, 8581-8591 10.1128/JVI.00533-12
47. Zimmermann, H. W.; Seidler, S.; Gassler, N.; Nattermann, J.; Luedde, T.; Trautwein, C.; Tacke, F. Interleukin-8 is activated in patients with chronic liver diseases and associated with hepatic macrophage accumulation in human liver fibrosis PLoS One 2011, 6, e21381 10.1371/journal.pone.0021381
48. Flisiak, R.; Feinman, S. V.; Jablkowski, M.; Horban, A.; Kryczka, W.; Pawlowska, M.; Heathcote, J. E.; Mazzella, G.; Vandelli, C.; Nicolas-Metral, V.; Grosgurin, P.; Liz, J. S.; Scalfaro, P.; Porchet, H.; Crabbe, R. The cyclophilin inhibitor Debio 025 combined with PEG IFNalpha2a significantly reduces viral load in treatment-naive hepatitis C patients Hepatology 2009, 49, 1460-1468 10.1002/hep.22835
49. Pan, Q.; Ramakrishnaiah, V.; Henry, S.; Fouraschen, S.; de Ruiter, P. E.; Kwekkeboom, J.; Tilanus, H. W.; Janssen, H. L.; van der Laan, L. J. Hepatic cell-to-cell transmission of small silencing RNA can extend the therapeutic reach of RNA interference (RNAi) Gut 2012, 61, 1330-1339 10.1136/gutjnl-2011-300449