Abstract
Hepatitis C virus (HCV) infection is a major worldwide problem that has emerged as one of the most significant diseases affecting humans. There are currently no vaccines or efficient therapies without side effects, despite today’s advanced medical technology. Currently, the common therapy for most patients (i.e. genotype 1) is combination of HCV-specific direct-acting antivirals (DAAs). Up to 2011, the standard of care (SOC) was a combination of peg-IFNα with ribavirin (RBV). After approval of NS3/4A protease inhibitor, SOC was peg-IFNα and RBV with either the first-generation DAAs boceprevir or telaprevir. In the past several years, various novel small molecules have been discovered and some of them (i.e., HCV polymerase, protease, helicase and entry inhibitors) have undergone clinical trials. Between 2013 and 2016, the second-generation DAA drugs simeprevir, asunaprevir, daclatasvir, dasabuvir, sofosbuvir, and elbasvir were approved, as well as the combinational drugs Harvoni®, Zepatier®, Technivie®, and Epclusa®. A number of reviews have been recently published describing the structure–activity relationship (SAR) in the development of HCV inhibitors and outlining current therapeutic approaches to hepatitis C infection. Target identification involves studying a drug’s mechanism of action (MOA), and a variety of target identification methods have been developed in the past few years. Chemical biology has emerged as a powerful tool for studying biological processes using small molecules. The use of chemical genetic methods is a valuable strategy for studying the molecular mechanisms of the viral lifecycle and screening for anti-viral agents. Two general screening approaches have been employed: forward and reverse chemical genetics. This review reveals information on the small molecules in HCV drug discovery by using chemical genetics for targeting the HCV protein and describes successful examples of targets identified with these methods.
Similar content being viewed by others
References
Ang MLT, Murima P, Pethe K (2015) Next-generation antimicrobials: from chemical biology to first-in-class drugs. Arch Pharmacal Res 38:1702–1717
Ares JMB, Duran-Pena MJ, Hernandez-Galan R, Collado IG (2013) Chemical genetics strategies for identification of molecular targets. Phytochem Rev 12:895–914
Baldick CJ, Wichroski MJ, Pendri A, Walsh AW, Fang J, Mazzucco CE, Pokornowski KA, Rose RE, Eggers BJ, Hsu M, Zhai W, Zhai G, Gerritz SW, Poss MA, Meanwell NA, Cockett MI, Tenny DJ (2010) A novel small molecule inhibitor of hepatitis C virus entry. PLoS Pathog 6(9):e1001086
Bartenschlager R, Lohmann V (2001) Novel cell culture systems for the hepatitis C virus. Antivir Res 52:1–17
Belda O, Targett-Adams P (2012) Small molecule inhibitors of the hepatitis C virus-encoded NS5A protein. Virus Res 170:1–14
Belema M, Meanwell NA (2014) Discovery of daclatasvir, a pan-genotypic hepatitis C virus NS5A replication complex inhibitor with potent clinical effect. J Med Chem 57:5057–5071
Belema M, Lopez OD, Bender JA, Romine JL, St Laurent DR, Langley DR, Lemm JA, O’Boyle DR, Sun JH, Wang C, Fridell RA, Meanwell NA (2014) Discovery and development of hepatitis C virus NS5A replication complex inhibitors. J Med Chem 57:1643–1672
Bryson PD, Cho NJ, Einav S, Lee C, Tai V, Bechtel J, Sivaraja M, Roberts C, Schmitz U, Glenn JS (2010) A small molecule inhibits HCV replication and alters NS4B’s subcellular distribution. Antivir Res 87:1–8
Buhler S, Bartenschlager R (2012) New targets for antiviral therapy of chronic hepatitis C. Liver Int 32(1):9–16
Cannalire RML, Barreca G Manfroni, Cecchetti V (2016) A journey around the medicinal chemistry of hepatitis C virus inhibitors targeting NS4B: from target to preclinical drug candidates. J Med Chem 59:16–41
Chang YT (2008) Forward chemical genetics. Wiley encyclopedia of chemical biology, pp 1–17
Chatel-Chaix L, Germain MA, Gotte M, Lamarre D (2012) Direct-acting and host-targeting HCV inhibitors: current and future directions. Curr Opin Virol 2:588–598
Choi H, Oh DC (2015) Considerations of the chemical biology of microbial natural products provide an effective drug discovery strategy. Arch Pharmacal Res 38:1591–1605
Choo QL, Kuo G, Weiner AJ, Overby LR, Bradley DW, Houghton M (1989) Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 244:359–362
Coburn CA, Meinke PT, Chang W, Fandozzi CM, Graham DJ, Hu B, Huang Q, Kargman S, Kozlowski J, Liu R, McCauley JA, Nomeir AA, Soll RM, Vacca JP, Wang D, Wu H, Zhong B, Olsen DB, Ludmerer SW (2013) Discovery of MK-8742: an HCV NS5A inhibitor with broad genotype activity. ChemMedChem 8:1930–1940
Crabbe R, Vuagniaux G, Dumont JM, Nicolas-Metral V, Marfurt J, Novaroli L (2009) An evaluation of the cyclophilin inhibitor Debio025 and its potential as a treatment for chronic hepatitis C. Expert Opin Investig Drugs 18:211–220
Das D, Hong J, Chen SH, Wang G, Beigelman L, Seiwert SD, Buckman BO (2011) Recent advances in drug discovery of benzothiadiazine and related analogs as HCV NS5B polymerase inhibitors. Bioorg Med Chem 19:4690–4703
Deeks ED (2016) Ombitasvir/paritaprevir/ritonavir plus dasabuvir: a review in chronic HCV genotype 1 infection. Drugs 75:1027–1038
DeGoey DA, Randolph JT, Liu D, Pratt J, Hutchins C, Donner P, Krueger AC, Matulenko M, Patel S, Motter CE, Nelson L, Keddy R, Tufano M, Caspi DD, Krishnan P, Mistry N, Koev G, Reisch TJ, Mondal R, Pilot-Matias T, Gao Y, Beno DW, Maring CJ, Molla A, Dumas E, Campbell A, Williams L, Collins C, Wagner R, Kati WM (2014) Discovery of ABT-267, a pan-genotypic inhibitor of HCV NS5A. J Med Chem 57:2047–2057
Einav S, Gerber D, Bryson PD, Sklan EH, Elazar M, Maerkl SJ, Glenn JS, Quake SR (2008) Discovery of a hepatitis C target and its pharmacological inhibitors by microfluidic affinity analysis. Nat Biotechnol 26:1019–1027
Einav S, Sobol HD, Gehrig E, Glenn JS (2010) The hepatitis C virus (HCV) NS4B RNA binding inhibitor clemizole is highly synergistic with HCV protease inhibitors. J Infect Dis 202:65–74
Fernandes F, Poole DS, Hoover S, Middleton R, Andrei AC, Gerstner J, Striker R (2007) Sensitivity of hepatitis C virus to cyclosporine A depends on nonstructural proteins NS5A and NS5B. Hepatology 46:1026–1033
Flisiak R, Dumont JM, Crabbe R (2007) Cyclophilin inhibitors in hepatitis C viral infection. Expert Opin Investig Drugs 16:1345–1354
Flisiak R, Horban A, Gallay P, Bobardt M, Selvarajah S, Wiercinska-Drapalo A, Siwak E, Cielniak I, Higersberger J, Kierkus J, Aeschlimann C, Grosqurin P, Nicolas-Metral V, Dumont JM, Porchet H, Crabbe R, Scalfaro P (2008) The cyclophilin inhibitor Debio-025 shows potent anti-hepatitis C effect in patients coinfected with hepatitis C and human immunodeficiency virus. Hepatology 47:817–826
Francesco RD, Carfi A (2007) Advances in the development of new therapeutic agents targeting the NS3-4A serine protease or the NS5B RNA-dependent RNA polymerase of the hepatitis C virus. Adv Drug Deliv Rev 59:1242–1262
Gao M, Nettles RE, Belema M, Snyder LB, Nguyen VN, Fridell RA, Serrano-Wu MH, Langley DR, Sun JH, O’Boyle DR, Lemm JA, Wang C, Knipe JO, Chien C, Colonno RJ, Grasela DM, Meanwell NA, Hamann LG (2010) Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect. Nature 465:96–100
Ghany MG, Strader DB, Thomas DL, Seeff LB (2009) Diagnosis, management, and treatment of hepatitis C: an update. Hepatology 49:1335–1374
Ghany MG, Nelson DR, Strader DB, Thomas DL, Seeff LB (2011) An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology 54:1433–1444
Goto K, Watashi K, Murata T, Hishiki T, Hijikata M, Shimotohno K (2006) Evaluation of the anti-hepatitis C virus effects of cyclophilin inhibitors, cyclosporin A, and NIM811. Biochem Biophys Res Commun 343:879–884
Greig SL (2016) Sofosbuvir/velpatasvir: a review in chronic hepatitis C. Drugs 76:1567–1578
Han Z, Liang X, Wang Y, Qing J, Cao L, Shang L, Yin Z (2016) The discovery of indole derivatives as novel hepatitis C virus inhibitors. Eur J Med Chem 116:147–155
Harper S, McCauley JA, Rudd MT, Ferrara M, DiFilippo M, Crescenzi B, Koch U, Petrocchi A, Holloway MK, Butcher JW, Romano JJ, Bush KJ, Gilbert KF, McIntyre CJ, Nguyen KT, Nizi E, Carroll SS, Ludmerer SW, Burlein C, DiMuzio JM, Graham DJ, McHale CM, Stahlhut MW, Olsen DB, Monteagudo E, Cianetti S, Giuliano C, Pucci V, Trainor N, Fandozzi CM, Rowley M, Coleman PJ, Vacca JP, Summa V, Liverton NJ (2012) Discovery of MK-5172, a macrocyclic hepatitis C virus NS3/4a protease inhibitor. ACS Med Chem Lett 3(4):332–336
Haudecoeur R, Peuchmaur M, Ahmed-Belkacem A, Pawlotsky JM, Boumendjel A (2013) Structure-activity relationships in the development of allosteric hepatitis C virus RNA-dependent RNA polymerase inhibitors: ten years of research. Med Res Rev 33(5):934–984
Hijikata M, Kato N, Ootsuyama Y, Nakagawa M, Shimotohno K (1991) Gene mapping of the putative structural region of the hepatitis C virus genome by in vitro processing analysis. Proc Natl Acad Sci USA 88:5547–5551
Jin G, Lee S, Choi M, Son S, Kim GW, Oh JW, Lee C, Lee K (2014) Chemical genetic-based discovery of indole derivatives as HCV NS5B polymerase inhibitors. Eur J Med Chem 75:413–425
Jung HJ, Kwon HJ (2015) Target deconvolution of bioactive small molecules: the heart of chemical biology and drug discovery. Arch Pharmacal Res 38:1627–1641
Kakarla R, Liu J, Naduthambi D, Chang W, Mosley RT, Bao D, Steuer HMM, Keilman M, Bansal S, Lam AM, Seibel W, Neilson S, Furman PA, Sofia MJ (2014) Discovery of a novel class of potent HCV NS4B inhibitors: SAR studies on piperazinone derivatives. J Med Chem 57:2136–2160
Kawasumi M, Nghiem P (2007) Chemical genetics: elucidating biological systems with small-molecule compounds. J Investig Dermatol 127:1577–1584
Keating GM (2015) Ledipasvir/sofosbuvir: a review of its use in chronic hepatitis C. Drugs 75:675–685
Keating GM (2016a) Daclatasvir: a review in chronic hepatitis C. Drugs 76:1381–1391
Keating GM (2016b) Elbasvir/grazoprevir: first global approval. Drugs 76:617–624
Keating GM (2016c) Ombitasvir/paritaprevir/ritonavir: a review in chronic HCV genotype 4 infection. Drugs 75:1203–1211
Keating GM, Vaidya A (2014) Sofosbuvir: first global approval. Drugs 74:273–282
Kim EJ, Yang I, Yoon YJ (2015) Developing Streptomyces venezuelae as a cell factory for the production of small molecules used in drug discovery. Arch Pharmacal Res 38:1606–1616
Koch U, Narjes F (2007) Recent progress in the development of inhibitors of the hepatitis C virus RNA-dependent RNA polymerase. Curr Top Med Chem 7:1302–1329
Kwon HJ, Kim Y, Sugihara Y, Baldetorp B, Welinder C, Watanabe K, Nishimura T, Malm J, Torok S, Dome B, Vegvari A, Gustavsson L, Fehniger TE, Marko-Varga G (2015) Drug compound characterization by mass spectrometry imaging in cancer tissue. Arch Pharmacal Res 38:1718–1727
Kwong AD, McNair L, Jacobson I, George S (2008) Recent progress in the development of selected hepatitis C virus NS3.4A protease and NS5B polymerase inhibitors. Curr Opin Pharmacol 8:522–531
Kwong AD, Kauffman RS, Hurter P, Mueller P (2011) Discovery and development of telaprevir: an NS3-4A protease inhibitor for treating genotype 1 chronic hepatitis C virus. Nat Biotechnol 29:993–1003
Lam AM, Espiritu C, Bansal S, Steuer HMM, Niu C, Zennou V, Keilman M, Zhu Y, Lan S, Otto MJ, Furman PA (2012) Genotype and subtype profiling of PSI-7977 as a nucleotide inhibitor of hepatitis C virus. Antimicrob Agents Chemother 56:3359–3368
LaPlante SR, Padyana AK, Abeywardane A, Bonneau P, Cartier M, Coulombe R, Jakalian A, Wildeson-Jones J, Li X, Liang S, McKercher G, White P, Zhang Q, Taylor SJ (2014) Integrated strategies for identifying leads that target the NS3 helicase of the hepatitis C virus. J Med Chem 57:2074–2090
Lavanchy D (2009) The global burden of hepatitis C. Liver Int 29(Suppl 1):74–81
Lee C (2011) Discovery of hepatitis C virus NS5A inhibitors as a new class of anti-HCV therapy. Arch Pharmacal Res 34(9):1403–1407
Lee J (2013) Cyclophilin A as a new therapeutic target for hepatitis C virus-induced hepatocellular carcinoma. Korean J Physiol Pharmacol 17:375–383
Lee C, Yang JS, Han G (2015) Identification of a thienopyrimidine derivatives target by a kinome and chemical biology approach. Arch Pharmacal Res 38:1575–1581
Lee R, Kottilil S, Wilson E (2016) Sofosbuvir/velpatasvir: a pangenotypic drug to simplify HCV therapy. Hep Int 11(2):161–170
Lemm JA, O’Boyle D, Liu M, Nower PT, Colonno R, Deshpande MS, Snyder LB, Martin SW, St Laurent DR, Serrano-Wu MH, Romine JL, Meanwell NA, Gao M (2010) Identification of hepatitis C virus NS5A inhibitors. J Virol 84:482–491
Li K, Frankowski KJ, Belon CA, Neuenswander B, Ndjomou J, Hanson AM, Shanahan MA, Schoene FJ, Blagg BSJ, Aube J, Frick DN (2012) Optimization of potent hepatitis C virus NS3 helicase inhibitors isolated from the yellow dyes thioflavine S and primuline. J Med Chem 55:3319–3330
Link JO, Taylor JG, Xu L, Mitchell M, Guo H, Liu H, Kato D, Kirschberg T, Sun J, Squires N, Parrish J, Keller T, Yang ZY, Yang C, Matles M, Wang Y, Wang K, Cheng G, Tian Y, Mogalian E, Mondou E, Cornpropst M, Perry J, Desai MC (2014) Discovery of ledipasvir (GS-5885): a potent, once-daily oral NS5A inhibitor for the treatment of hepatitis C virus infection. J Med Chem 57:2033–2046
Lohmann V, Korner F, Koch J, Herian U, Theilmann L, Bartenschlager R (1999) Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line. Science 285:110–113
Lv J, Shim JS (2015) Existing drugs and their application in drug discovery targeting cancer stem cells. Arch Pharmacal Res 38:1617–1626
Macalino SJY, Gosu V, Hong S, Choi S (2015) Role of computer-aided drug design in modern drug discovery. Arch Pharmacal Res 38:1686–1701
Maerkl SJ, Quake SR (2007) A systems approach to measuring the binding energy landscapes of transcription factors. Science 315:233–237
Mayhoub AS (2012) Hepatitis C RNA-dependent RNA polymerase inhibitors: a review of structure-activity and resistance relationships; different scaffolds and mutations. Bioorg Med Chem 20:3150–3161
McCauley JA, McIntyre CJ, Rudd MT, Nguyen KT, Romano JJ, Butcher JW, Gilbert KF, Bush KJ, Holloway MK, Swestock J, Wan BL, Carroll SS, DiMuzio JM, Graham DJ, Ludmerer SW, Mao SS, Stahlhut MW, Fandozzi CM, Trainor N, Olsen DB, Vacca JP, Liverton NJ (2010) Discovery of vaniprevir (MK-7009), a macrocyclic hepatitis C virus NS3/4a protease inhibitor. J Med Chem 53:2443–2463
Miller JF, Chong PY, Shotwell JB, Catalano JG, Tai VW, Fang J, Banka AL, Roberts CD, Youngman M, Zhang H, Xiong Z, Mathis A, Pouliot JJ, Hamatake RK, Price DJ, Seal JW, Stroup LL, Creech KL, Carballo LH, Todd D, Spaltenstein A, Furst S, Hong Z, Peat AJ (2014) Hepatitis C replication inhibitors that target the viral NS4B protein. J Med Chem 57:2107–2120
Mir F, Kahveci AS, Ibdah JA, Tahan V (2017) Sofosbuvir/velpatasvir regimen promises an effective pan-genotypic hepatitis C virus cure. Drug Des Dev Ther 11:497–502
Mizokami M, Yokosuka O, Takehara T, Sakamoto N, Korenaga M, Mochizuki H, Nakane K, Enomoto H, Ikeda F, Yanase M, Toyoda H, Genda T, Umemura T, Yatsuhashi H, Ide T, Toda N, Nirei K, Ueno Y, Nishigaki Y, Betular J, Gao B, Ishizaki A, Omote M, Mo H, Garrison K, Pang PS, Knox SJ, Symonds WT, McHutchison JG, Izumi N, Omata M (2015) Ledipasvir and sofosbuvir fixed-dose combination with and without ribavirin for 12 weeks in treatment-naïve and previously treated Japanese patients with genotype 1 hepatitis C: an open-label, randomised, phase 3 trial. Lancet Infect Dis. doi:10.1016/S1473-3099(15)70099-X
Naik R, Han S, Lee K (2015) Chemical biology approach for the development of hypoxia inducible factor (HIF) inhibitor LW6 as a potential anticancer agent. Arch Pharmacal Res 38:1563–1574
Nakano T, Lau GMG, Lau GML, Sugiyama M, Mizokami M (2012) An updated analysis of hepatitis C virus genotypes and subtypes based on the complete coding region. Liver Int 32:339–345
Neumann G, Hatta M, Kawaoka Y (2003) Reverse genetics for the control of avian influenza. Avian Dis 47:882–887
O’ Connor CJ, Laraia L, Spring DR (2011) Chemical genetics. Chem Soc Rev 40:4332–4345
Patil VM, Gupta SP, Samanta S, Masand N (2011) Current perspective of HCV NS5B inhibitors: a review. Curr Med Chem 18:5564–5597
Pawlotsky JM, Chevaliez S, McHutchison JG (2007) The hepatitis C virus life cycle as a target for new antiviral therapies. Gastroenterology 132:1979–1998
Phillips B, Cai R, Delaney W, Du Z, Ji M, Jin H, Lee J, Li J, Niedziela-Majka A, Mish M, Pyun HJ, Saugier J, Tirunagari N, Wang J, Yang H, Wu Q, Sheng C, Zonte C (2014) Highly potent HCV NS4B inhibitors with activity against multiple genotypes. J Med Chem 57:2161–2166
Qian XJ, Zhu YZ, Zhao P, Qi ZT (2016) Entry inhibitors: new advances in HCV treatment. Emerg Microbes Infect 5:e3
Rai R, Deval J (2011) New opportunities in anti-hepatitis C virus drug discovery: targeting NS4B. Antivir Res 90:93–101
Raney KD, Sharma SD, Moustafa IM, Cameron CE (2010) Hepatitis C virus non-structural protein 3 (HCV NS3): a multifunctional antiviral target. J Biol Chem 285(30):22725–22731
Rehman S, Ashfaq UA, Javed T (2011) Antiviral drugs against hepatitis C virus. Genet Vaccines Ther 9:11
Rosenquist Å, Samuelsson B, Johansson PO, Cummings MD, Lenz O, Raboisson P, Simmen K, Vendeville S, de Kock H, Nilsson M, Horvath A, Kalmeijer R, de la Rosa G (2014) Discovery and development of simeprevir (TMC435), a HCV NS3/4A protease inhibitor. J Med Chem 57:1673–1693
Salam KA, Akimitsu N (2013) Hepatitis C virus NS3 inhibitors: current and future perspectives. Biomed Res Int 2013:467869
Schaefer EAK, Chung RT (2012) Anti-hepatitis C virus drugs in development. Gastroenterology 142:1340–1350
Schreiber SL (2000) Target-oriented and diversity-oriented organic synthesis in drug discovery. Science 287:1964–1969
Scola PM, Sun LQ, Wang AX, Chen J, Sin N, Venables BL, Sit SY, Chen Y, Cocuzza A, Bilder DM, D’Andea SV, Zheng B, Hewawasam P, Tu Y, Friborg J, Falk P, Hernandez D, Levine S, Chen C, Yu F, Sheaffer AK, Zhai G, Barry D, Knipe JO, Han YH, Schartman R, Donoso M, Mosure K, Sinz MW, Zvyaga T, Good AC, Rajamani R, Kish K, Tredup J, Klei HE, Gao Q, Mueller L, Colonno RJ, Grasela DM, Adams SP, Loy J, Levesque PC, Sun H, Shi H, Sun L, Warner W, Li D, Zhu J, Meanwell NA, McPhee F (2014) The discovery of asunaprevir (BMS-650032), an orally efficacious NS3 protease inhibitor for the treatment of hepatitis C virus infection. J Med Chem 57:1730–1752
Seo YH (2015) Organelle-specific Hsp90 inhibitors. Arch Pharmacal Res 38:1582–1590
Shotwell JB, Baskaran S, Chong P, Creech KL, Crosby RM, Dickson H, Fang J, Garrido D, Mathis A, Maung J, Parks DJ, Pouliot JJ, Price DJ, Rai R, Seal JW, Schmitz U, Tai VWF, Thomson M, Xie M, Xiong ZPZ, Peat AJ (2012) Imidazo[1,2-a]pyridines that directly interact with hepatitis C NS4B: initial preclinical characterization. ACS Med Chem Lett 3:565–569
Sofia MJ, Bao D, Chang W, Du J, Nagarathanam D, Rachakonda S, Reddy PG, Ross BS, Wang P, Zhang HR, Bansal S, Espiritu C, Keilman M, Lam AM, Steuer HMM, Niu C, Otto MJ, Furman PA (2010) Discovery of a β-d-2′-deoxy-2′-α-fluoro-2′-β-C-methyluridine nucleotide prodrug (PSI-7977) for the treatment of hepatitis C virus. J Med Chem 53:7202–7218
Spring DR (2005) Chemical genetics to chemical genomics: small molecules offer big insights. Chem Soc Rev 34:472–482
Stirnimann G (2014) Ombitasvir (ABT-267), a novel NS5A inhibitor for the treatment of hepatitis C. Expert Opin Pharmacother 15(17):2609–2622
Tai VWF, Garrido D, Price DJ, Maynard A, Pouliot JJ, Xiong Z, Seal JW, Creech KL, Kryn LH, Baughman TM, Peat AJ (2014) Design and synthesis of spirocyclic compounds as HCV replication inhibitors by targeting viral NS4B protein. Bioorg Med Chem Lett 24:2288–2294
Tan SL, Pause A, Shi Y, Sonenberg N (2002) Hepatitis C therapeutics: current status and emerging strategies. Nat Rev Drug Discov 1:867–881
Tang H (2010) Cyclophilin inhibitors as a novel HCV therapy. Viruses 2:1621–1634
Tashiro E, Imoto M (2015) Chemical biology of compounds obtained from screening using disease models. Arch Pharmacal Res 38:1651–1660
Trivella JP, Gutierrez J, Martin P (2015) Dasabuvir: a new direct antiviral agent for the treatment of hepatitis C. Expert Opin Pharmacother 16(4):617–624
Venkatraman S (2012) Discovery of boceprevir, a direct-acting NS3/4A protease inhibitor for treatment of chronic hepatitis C infections. Trends Pharmacol Sci 33:289–294
Wang C, Gale M Jr, Keller BC, Huang H, Brown MS, Goldstein JL, Ye J (2005) Identification of FBL2 as a geranylgeranylated cellular protein required for hepatitis C virus RNA replication. Mol Cell 18(4):425–434
Wang NY, Xu Y, Zuo WQ, Xiao KJ, Liu L, Zeng XX, You XY, Zhang LD, Gao C, Liu ZH, Ye TH, Xia Y, Xiong Y, Song XJ, Lei Q, Peng CT, Tang H, Yang SY, Wei YQ, Yu LT (2015) Discovery of imidazo[2,1-b]thiazole HCV NS4B inhibitors exhibiting synergistic effect with other direct-acting antiviral agents. J Med Chem 58:2764–2778
Watashi K, Shimotohno K (2007) Chemical genetics approach to hepatitis C virus replication: cyclophilin as a target for anti-hepatitis C virus strategy. Rev Med Virol 17:245–252
Watashi K, Hijikata M, Hosaka M, Yamaji M, Shimotohno K (2003) Cyclosporin A suppresses replication of hepatitis C virus genome in cultured hepatocytes. Hepatology 38:1282–1288
Watashi K, Ishii N, Hijikata M, Inoue D, Murata T, Miyanari Y, Shimotohno K (2005) Cyclophilin B is a functional regulator of hepatitis C virus RNA polymerase. Mol Cell 19:111–122
Wong-Staal F, Syder AJ, McKelvy JF (2010) Targeting HCV entry for development of therapeutics. Viruses 2:1718–1733
Yang S, Jyothi KR, Lim S, Choi TG, Kim JH, Akter S, Jang M, Ahn HJ, Kim HY, Windisch MP, Khadka DB, Zhao C, Jin Y, Kang I, Ha J, Oh BC, Kim M, Kim SS, Cho WJ (2015) Structure-based discovery of novel cyclophilin A inhibitors for the treatment of hepatitis C virus infections. J Med Chem 58:9546–9561
Zhang X, Zhang N, Chen G, Turpoff A, Ren H, Takasugi J, Morrill C, Zhu J, Li C, Lennox W, Paget S, Liu Y, Almstead N, Njoroge FG, Gu Z, Komatsu T, Clausen V, Espiritu C, Graci J, Colacino J, Lahser F, Risher N, Weetall M, Nomeir A, Karp GM (2013) Discovery of novel HCV inhibitors: synthesis and biological activity of 6-(indol-2-yl)pyridine-3-sulfonamides targeting hepatitis C virus NS4B. Bioorg Med Chem Lett 23:3947–3953
Zhang N, Zhang X, Zhu J, Turpoff A, Chen G, Morrill C, Huang S, Lennox W, Liu R, Kakarla R, Li C, Ren H, Almstead N, Venkatraman S, Njoroge FG, Gu Z, Clausen V, Graci J, Jung SP, Zheng Y, Colacino JM, Lahser F, Sheedy J, Mollin A, Weetall M, Nomeir A, Karp GM (2014) Structure-activity relationship (SAR) optimization of 6-(indol-2-yl)pyridine-3-sulfonamides: identification of potent, selective, and orally bioavailable small molecules targeting hepatitis C (HCV) NS4B. J Med Chem 57:2121–2135
Zhao C, Wang Y, Ma S (2015) Recent advances on the synthesis of hepatitis C virus NS5B RNA-dependent RNA-polymerase inhibitors. Eur J Med Chem 102:188–214
Zheng W, Li G, Li X (2015) Affinity purification in target identification: the specificity challenge. Arch Pharmacal Res 38:1661–1685
Zhu Y, Xiao T, Lei S, Zhou F, Wang MW (2015) Application of chemical biology in target identification and drug discovery. Arch Pharmacal Res 38:1642–1650
Acknowledgements
This work was supported by the Dongguk University Research Fund of 2016.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Jin, G., Lee, J. & Lee, K. Chemical genetics-based development of small molecules targeting hepatitis C virus. Arch. Pharm. Res. 40, 1021–1036 (2017). https://doi.org/10.1007/s12272-017-0949-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12272-017-0949-3