药学学报, 2020, 55(4): 652-668
引用本文:
宋淑, 高萍, 展鹏, 刘新泳. 丙型肝炎病毒抑制剂研究进展[J]. 药学学报, 2020, 55(4): 652-668.
SONG Shu, GAO Ping, ZHAN Peng, LIU Xin-yong. Recent progress in inhibitors against hepatitis C virus[J]. Acta Pharmaceutica Sinica, 2020, 55(4): 652-668.

丙型肝炎病毒抑制剂研究进展
宋淑, 高萍, 展鹏, 刘新泳
山东大学药学院药物化学研究所, 化学生物学教育部重点实验室, 山东 济南 250012
摘要:
丙型肝炎病毒(hepatitis C virus,HCV)感染是全球性的公共卫生问题之一,全世界有1.3亿至1.5亿人长期感染,其中四分之一的患者会产生肝硬化、肝细胞癌甚至肝功能衰竭等并发症。完全清除病毒是研究者不断进行抗丙肝新药物研发的目标与动力。本综述精选近几年具代表性的研究实例,从药物化学的视角总结了抗丙肝小分子抑制剂的前沿进展。
关键词:    丙型肝炎      抗病毒药物      药物靶标      药物设计      小分子抑制剂     
Recent progress in inhibitors against hepatitis C virus
SONG Shu, GAO Ping, ZHAN Peng, LIU Xin-yong
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology(Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China
Abstract:
Hepatitis C virus (HCV) infection is one of the global public health issues. Approximately, 130-150 million individuals are chronically infected worldwide and a quarter of these patients are at increased risk of developing liver cirrhosis, hepatocellular carcinoma and even liver failure. A complete eradication of the virus is one of the most important treatment goals for antiviral research. From the point of view of medicinal chemistry, we summarize and discuss current endeavors towards the discovery and development of novel inhibitors with various scaffolds or distinct mechanisms of action.
Key words:    hepatitis C virus    antiviral drug    drug target    drug design    small molecule inhibitor   
收稿日期: 2019-09-29
DOI: 10.16438/j.0513-4870.2019-0786
基金项目: 国家自然科学基金资助项目(81420108027,81573347);山东省重点研发计划(2017CXGC1401,2019JZZY021011).
通讯作者: 展鹏,Tel:86-531-88380270,E-mail:zhanpeng1982@sdu.edu.cn;刘新泳,E-mail:xinyongl@sdu.edu.cn
Email: zhanpeng1982@sdu.edu.cn;xinyongl@sdu.edu.cn
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参考文献:
[1] World Health Organization. Hepatitis C[EB/OL]. 2018[2019-10]. http://www.searo.who.Int/thailand/factsheets/fs0018/en/.
[2] Alazard-Dany N, Denolly S, Boson B, et al. Overview of HCV life cycle with a special focus on current and possible future antiviral targets[J]. Viruses, 2019, 11:30.
[3] Wang J, He XY. Anti-hepatitis C virus drugs:research advances[J]. J Int Pharm Res(国际药学研究杂志), 2015, 42:551-560.
[4] Manns MP, Foster GR, Rockstroh JK, et al. The way forward in HCV treatment--finding the right path[J]. Nat Rev Drug Discov, 2007, 6:991-1000.
[5] Zając M, Muszalska I, Sobczak A, et al. Hepatitis C-new drugs and treatment prospects[J]. Eur J Med Chem, 2019, 165:225-249.
[6] Li G, De Clercq E. Current therapy for chronic hepatitis C:The role of direct-acting antivirals[J]. Antiviral Res, 2017, 142:83-122.
[7] Horner SM, Gale M. Regulation of hepatic innate immunity by hepatitis C virus[J]. Nat Med, 2013, 19:879-888.
[8] Hayes CN, Chayama K. Emerging treatments for chronic hepatitis C[J]. J Formos Med Assoc, 2015, 114:204-215.
[9] Rusere LN,Matthew AN, Lockbaum GJ, et al. Quinoxaline-based linear HCV NS3/4A protease inhibitors exhibit potent activity against drug resistant variants[J]. ACS Med Chem Lett, 2018, 9:691-696.
[10] Wang AX, Chen J, Zhao Q, et al. Structure-activity relationships of 4-hydroxy-4-biaryl-proline acylsulfonamide tripeptides:a series of potent NS3 protease inhibitors for the treatment of hepatitis C virus[J]. Bioorg Med Chem Lett, 2017, 27:590-596.
[11] Scola PM, Sun LQ, Wang AX, et al. The discovery of asunaprevir (BMS-650032), an orally efficacious NS3 protease inhibitor for the treatment of hepatitis C virus infection[J]. J Med Chem, 2014, 57:1730-1752.
[12] Gising J, Belfrage AK, Alogheli H, et al. Achiral pyrazinone-based inhibitors of the hepatitis C virus NS3 protease and drug-resistant variants with elongated substituents directed toward the S2 pockect[J]. J Med Chem, 2014, 57:1790-1801.
[13] Belfrage AK, Abdurakhmanov E, Åkerblom E, et al. Pan-NS3 protease inhibitors of hepatitis C virus based on an R3-elongated pyrazinone scaffold[J]. Eur J Med Chem, 2018, 148:453-464.
[14] Zheng B, D'Andrea SV, Sun LQ, et al. Potent inhibitors of hepatitis C virus NS3 protease:employment of a difluoromethyl group as a hydrogen-bond donor[J]. ACS Med Chem Lett, 2018, 9:143-148.
[15] Shah U, Jayne C, Chackalamannil S, et al. Novel quinoline-based P2-P4 macrocyclic derivatives as pan-genotypic HCV NS3/4a protease inhibitors[J]. ACS Med Chem Lett, 2014, 5:264-269.
[16] Neelamkavil SF, Agrawal S, Bara T, et al. Discovery of MK-8831, a novel spiro-proline macrocycle as a pan-genotypic HCV-NS3/4a protease inhibitor[J]. ACS Med Chem Lett, 2015, 7:111-116.
[17] Velázquez F, Chelliah M, Clasby M, et al. Design and synthesis of P2-P4 macrocycles containing a unique spirocyclic proline:a new class of HCV NS3/4A inhibitors[J]. ACS Med Chem Lett, 2016, 7:1173-1178.
[18] Pawlotsky JM. Hepatitis C virus resistance to direct-acting antiviral drugs in interferon-free regimens[J]. Gastroenterology, 2016, 151:70-86.
[19] Matthew AN, Zephyr J, Hill CJ, et al. Hepatitis C virus NS3/4A protease inhibitors incorporating flexible P2 quinoxalines target drug resistant viral variantsc[J]. J Med Chem, 2017, 60:5699-5716.
[20] Yang H, Yang C, Wang Y, et al. Preclinical characterization of the novel HCV NS3 protease inhibitor GS-9256[J]. Antivir Ther, 2017, 22:413-420.
[21] Sheng XC, Casarez A, Cai RC, et al. Discovery of GS-9256:a novel phosphinic acid derived inhibitor of the hepatitis C virus NS3/4A protease with potent clinical activity[J]. Bioorg Med Chem Lett, 2012, 22:1394-1396.
[22] Bowsher M, Hiebert S, Li R, et al. The discovery and optimization of naphthalene-linked P2-P4 Macrocycles as inhibitors of HCV NS3 protease[J]. Bioorg Med Chem Lett, 2018, 28:43-48.
[23] Watkins WJ, Ray AS, Chong LS. HCV NS5B polymerase inhibitors[J]. Curr Opin Drug Discov Devel, 2010, 13:441-465.
[24] Membreno FE, Lawitz EJ. The HCV NS5B nucleoside and non-nucleoside inhibitors[J]. Clin Liver Dis, 2011, 15:611-626.
[25] Hedskog C, Dvory-Sobol H, Gontcharova V, et al. Evolution of the HCV viral population from a patient with S282T detected at relapse after sofosbuvir monotherapy[J]. J Viral Hepat, 2015, 22:871-881.
[26] Zhen L, Dai L, Wen X, et al. Discovery of novel nucleotide prodrugs with improved potency against HCV variants carrying NS5B S282T mutation[J]. J Med Chem, 2017, 60:6077-6088.
[27] Zhou S, Mahmoud S, Liu P, et al. 2'-Chloro,2'-fluoro ribonucleotide prodrugs with potent pan-genotypic activity against hepatitis C virus replication in culture[J]. J Med Chem, 2017, 60:5424-5437.
[28] Jonckers TH, Vandyck K, Vandekerckhove L, et al. Nucleotide prodrugs of 2'-deoxy-2'-spirooxetane ribonucleosides as novel inhibitors of the HCV NS5B polymerase[J]. J Med Chem, 2014, 57:1836-1844.
[29] Jonckers TH, Tahri A, Vijgen L, et al. Discovery of 1-((2R,4aR,6R,7R,7aR)-2-isopropoxy-2-oxidodihydro-4H,6H-spiro[furo[3,2-d] [1,3,2] dioxaphosphinine-7,2'-oxetan]-6-yl)pyrimidine-2,4(1H,3H)-dione (JNJ-54257099), a 3'-5'-cyclic phosphate ester prodrug of 2'-deoxy-2'-spirooxetane uridine triphosphate useful for HCV inhibition[J]. J Med Chem, 2016, 59:5790-5798.
[30] Cheng Y, Shen J, Peng RZ, et al. Structure-based optimization and derivatization of 2-substituted quinolone-based non-nucleoside HCV NS5B inhibitors with submicromolar cellular replicon potency[J]. Bioorg Med Chem Lett, 2016, 26:2900-2906.
[31] Manfroni G, Cannalire R, Barreca ML, et al. The versatile nature of the 6-aminoquinolone scaffold:identification of submicromolar hepatitis C virus NS5B inhibitors[J]. J Med Chem, 2014, 57:1952-1963.
[32] Court JJ, Poisson C, Ardzinski A, et al. Discovery of novel thiophene-based, thumb pocket 2 allosteric inhibitors of the hepatitis C NS5B polymerase with improved potency and physicochemical profiles[J]. J Med Chem, 2016, 59:6293-6302.
[33] Li P, Dorsch W, Lauffer DJ, et al. Discovery of novel allosteric HCV NS5B inhibitors. 2. Lactam-containing thiophene carboxylates[J]. ACS Med Chem Lett, 2017, 8:251-255.
[34] Barnes-Seeman D, Boiselle C. Design and synthesis of lactam-thiophene carboxylic acids as potent hepatitis C virus polymerase inhibitors[J]. Bioorg Med Chem Lett, 2014, 24:3979-3985.
[35] Yeung KS, Beno BR, Parcella K, et al. Discovery of a hepatitis C Virus NS5B replicase palm site allosteric inhibitor (BMS-929075) advanced to Phase 1 clinical studies[J]. J Med Chem, 2017, 60:4369-4385.
[36] Eastman KJ, Parcella K, Yeung KS, et al. The discovery of a pan-genotypic, primer grip inhibitor of HCV NS5B polymerase[J]. Med Chem Commun, 2017, 8:796-806.
[37] Parcella K, Eastman K, Yeung KS, et al. Improving metabolic stability with deuterium:the discovery of BMT-052, a pan-genotypic HCV NS5B polymerase inhibitor[J]. ACS Med Chem Lett, 2017, 8:771-774.
[38] Meguellati A, Ahmed-Belkacem A, Nurisso A, et al. New pseudodimeric aurones as palm pocket inhibitors of hepatitis C virus RNA-dependent RNA polymerase[J]. Eur J Med Chem, 2016, 115:217-229.
[39] Randolph JT, Krueger AC, Donner PL, et al. Synthesis and biological characterization of aryl uracil inhibitors of hepatitis C virus NS5B polymerase:discovery of ABT-072, a trans-stilbene analog with good oral bioavailability[J]. J Med Chem, 2018, 61:1153-1163.
[40] Camarasa M,Puig de la Bellacasa R, González ÀL, et al. Design, synthesis and biological evaluation of pyrido[2,3-d]pyrimidin-7-(8H)-ones as HCV inhibitors[J]. Eur J Med Chem, 2016, 115:463-483.
[41] Kaushik-Basu N, Ratmanova NK, Manvar D, et al. Bicyclic octahydrocyclohepta[b]pyrrol-4(1H)-one derivatives as novel selective anti-hepatitis C virus agents[J]. Eur J Med Chem, 2016, 122:319-325.
[42] Belema M, Meanwell NA. Discovery of daclatasvir, a pan-genotypic hepatitis C virus NS5A replication complex inhibitor with potent clinical effect[J]. J Med Chem, 2014, 57:5057-5071.
[43] Bachand C, Belema M, Deon DH, et al. Hepatitis C virus inhibitors:US, 021927[P]. 2008-11-27.
[44] Bachand C, Belema M, Deon DH, et al. Hepatitis C virus inhibitors:US, 021928[P]. 2008-12-04.
[45] Bachand C, Belema M, Deon DH, et al. Hepatitis C virus inhibitors:US, 021936[P]. 2008-12-18.
[46] Li L, Zhong M. Inhibitors of HCV NS 5A:US, 065668[P]. 2010-06-26.
[47] Zhong M, Li L. Inhibitors of HCV NS 5A:US, 102010[P]. 2010-06-10.
[48] Li L, Zhong M. Inhibitors of HCV NS 5A:US, 065681[P]. 2008-12-03.
[49] Guo H, Kato D, Kirschberg TA, et al. Antiviral compounds:US, 092010[P]. 2010-12-09.
[50] Belema M, Lopez OD, Bender JA, et al. Discovery and development of hepatitis C virus NS5A replication complex inhibitors[J]. J Med Chem, 2014, 57:1643-1672.
[51] Ivachtchenko AV, Mitkin OD, Yamanushkin PM, et al. Discovery of novel highly potent hepatitis C virus NS5A inhibitor (AV4025)[J]. J Med Chem, 2014, 57:7716-7730.
[52] DeGoey DA, Randolph JT, Liu D, et al. Discovery of ABT-267, a pan-genotypic inhibitor of HCV NS5A[J]. J Med Chem, 2014, 57:2047-2057.
[53] Franz AK, Wilson SO. Organosilicon molecules with medicinal applications[J]. J Med Chem, 2012, 56:388-405.
[54] Lazareva N, Lazarev I. Drug design based on the carbon/silicon switch strategy[J]. Russ Chem Bull, 2015, 64:1221-1232.
[55] Nair AG, Zeng Q, Selyutin O, et al. Discovery of silyl proline containing HCV NS5A inhibitors with pan-genotype activity:SAR development[J]. Bioorg Med Chem Lett, 2016, 26:1475-1479.
[56] Liu B, Gai K, Qin H, et al. Design, synthesis and identification of silicon-containing HCV NS5A inhibitors with pan-genotype activity[J]. Eur J Med Chem, 2018, 148:95-105.
[57] Coburn CA, Meinke PT, Chang W, et al. Discovery of MK-8742:an HCV NS5A inhibitor with broad genotype activity[J]. ChemMedChem, 2013, 8:1930-1940.
[58] Rockstroh JK, Nelson M, Katlama C, et al. Efficacy and safety of grazoprevir (MK-5172) and elbasvir (MK-8742) in patients with hepatitis C virus and HIV co-infection (C-EDGE CO-INFECTION):a non-randomised, open-label trial[J]. Lancet HIV, 2015, 2:e319-27.
[59] Tong L, Yu W, Chen L, et al. Discovery of ruzasvir (MK-8408):a potent, pan-genotype HCV NS5A inhibitor with optimized activity against common resistance-associated polymorphisms[J]. J Med Chem, 2017, 60:290-306.
[60] Lawitz E, Gane E, Feld JJ, et al. Efficacy and safety of a two-drug direct-acting antiviral agent regimen ruzasvir 180 mg and uprifosbuvir 450 mg for 12 weeks in adults with chronic hepatitis C virus genotype 1, 2, 3, 4, 5 or 6[J]. J Viral Hepat, 2019, 26:1127-1138.
[61] Kazmierski WM, Maynard A, Duan M, et al. Novel spiroketal pyrrolidine GSK2336805 potently inhibits key hepatitis C virus genotype 1b mutants:from lead to clinical compound[J]. J Med Chem, 2014, 57:2058-2073.
[62] Vijgen L, Thys K, Vandebosch A, et al. Virology analysis in HCV genotype 1-infected patients treated with the combination of simeprevir and TMC647055/ritonavir, with and without ribavirin, and JNJ-56914845[J]. Virol J, 2017, 14:101.
[63] Dwyer MP, Keertikar KM, Chen L, et al. Matched and mixed cap derivatives of the HCV NS5A inhibitor MK-8742[J]. Bioorg Med Chem Lett, 2016, 26:4106-4111.
[64] Yu W, Zhou G, Coburn CA, et al. Substituted tetracyclic indole core derivatives of HCV NS5A inhibitor MK-8742[J]. Bioorg Med Chem Lett, 2016, 26:4851-4856.
[65] Tong L, Yu W, Coburn CA, et al. Structure-activity relationships of proline modifications around the tetracyclic-indole class of NS5A inhibitors[J]. Bioorg Med Chem Lett, 2016, 26:5354-5360.
[66] Yu W, Tong L, Hu B, et al. Discovery of chromane containing HCV NS5A inhibitors with improved potency against resistance associate variants[J]. J Med Chem, 2016, 59:10228-10243.
[67] Yu W, Tong L, Selyutin O, et al. Discovery of MK-6169, a potent pan-genotype hepatitis C virus NS5A inhibitor with optimized activity against common resistance-associated substitutions[J]. J Med Chem, 2018, 61:3984-4003.
[68] Bae IH, Choi JK, Chough C, et al. Potent hepatitis C virus NS5A inhibitors containing a benzidine core[J]. ACS Med Chem Lett, 2013, 5:255-258.
[69] Bae IH, Kim HS, You Y, et al. Novel benzidine and diaminofluorene prolinamide derivatives as potent hepatitis C virus NS5A inhibitors[J]. Eur J Med Chem, 2015, 101:163-178.
[70] You Y, Kim HS, Bae IH, et al. New potent biaryl sulfate-based hepatitis C virus inhibitors[J]. Eur J Med Chem, 2017, 125:87-100.
[71] Yeh TK, Kang IJ, Hsu TA, et al. A novel, potent, and orally bioavailable thiazole HCV NS5A inhibitor for the treatment of hepatitis C virus[J]. Eur J Med Chem, 2019, 167:245-268.
[72] Wagner R, Randolph JT, Patel SV, et al. Highlights of the structure-activity relationships of benzimidazole linked pyrrolidines leading to the discovery of the hepatitis C virus NS5A inhibitor pibrentasvir (ABT-530)[J]. J Med Chem, 2018, 61:4052-4066.
[73] Foster GR, Dore GJ, Wang S, et al. Glecaprevir/pibrentasvir in patients with chronic HCV and recent drug use:an integrated analysis of 7 phase III studies[J]. Drug Alcohol Depend, 2019, 194:487-494.
[74] Kang IJ, Hsu SJ, Yang HY, et al. Potent, selective, and orally bioavailable HCV NS5A inhibitor for treatment of hepatitis C virus:(S)-1-((R)-2-(cyclopropanecarboxamido)-2-phenylacetyl)-N-(4-phenylthiazol-2-yl)pyrrolidine-2-carboxamide[J]. J Med Chem, 2017, 60:228-247.
[75] Neklesa TK, Winkler JD, Crews CM. Targeted protein degradation by PROTACs[J]. Pharmacol Ther, 2017, 174:138-144.
[76] De Wispelaere M, Du G, Donovan KA, et al. Small molecule degraders of the hepatitis C virus protease reduce susceptibility to resistance mutations[J]. Nat Commun, 2019, 10:3468.
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