药学学报, 2020, 55(4): 669-678
引用本文:
侯凌欣, 鞠翰, 展鹏, 刘新泳. 抗登革病毒药物化学研究新进展[J]. 药学学报, 2020, 55(4): 669-678.
HOU Ling-xin, JU Han, ZHAN Peng, LIU Xin-yong. Recent advances in the discovery of dengue virus inhibitors[J]. Acta Pharmaceutica Sinica, 2020, 55(4): 669-678.

抗登革病毒药物化学研究新进展
侯凌欣, 鞠翰, 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:
登革热是由埃及伊蚊和白纹伊蚊传播的一种虫媒病毒的疾病。登革病毒感染能够引发登革热、登革出血热和登革休克综合征等多种症状。迄今为止尚无治疗登革病毒感染的特异性药物上市。本文结合抗登革病毒研究的最新进展,从蛋白酶抑制剂、病毒多聚酶抑制剂、病毒侵入抑制剂、病毒复制相关宿主因子抑制剂以及衣壳蛋白抑制剂等几个方面综述了抗登革病毒药物研究新进展。
关键词:    登革热      登革热病毒      登革出血热      药物发现     
Recent advances in the discovery of dengue virus inhibitors
HOU Ling-xin, JU Han, 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:
Dengue fever is one of the most important vector-borne human diseases caused by mosquito vector Aedes aegypti and Aedes albopictus. Dengue virus can cause dengue fever, dengue hemorrhagic fever and dengue shock syndrome. There are no approved drugs for the treatment of dengue disease so far. In this paper, combined with the latest progress in the research of anti-dengue virus, the new progress in the research of anti-dengue virus drugs was reviewed from the aspects of protease inhibitors, virus polymerase inhibitors, entry inhibitors, virus replication-related host factor inhibitors, capsid protein inhibitors and nucleic acid inhibitors.
Key words:    dengue fever    dengue virus    dengue hemorrhagic fever    drug discovery   
收稿日期: 2019-09-29
DOI: 10.16438/j.0513-4870.2019-0787
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:86-531-88382005,E-mail:zhanpeng1982@sdu.edu.cn;刘新泳,E-mail:xinyongl@sdu.edu.cn
Email: zhanpeng1982@sdu.edu.cn;xinyongl@sdu.edu.cn
相关功能
PDF(703KB) Free
打印本文
0
作者相关文章
侯凌欣  在本刊中的所有文章
鞠翰  在本刊中的所有文章
展鹏  在本刊中的所有文章
刘新泳  在本刊中的所有文章

参考文献:
[1] Martina BE, Koraka P, Osterhaus AD. Dengue virus pathogenesis:an integrated view[J]. Clin Microbiol Rev, 2009, 22:564-581.
[2] Uno N, Ross TM. Dengue virus and the host innate immune response[J]. Emerg Microbes Infect, 2018, 7:1-11.
[3] Green J, Bandarage U, Luisi K, et al. Recent advances in the discovery of dengue virus inhibitors[J]. Annu Rep Med Chem, 2012, 47:297-317.
[4] Muller DA, Young PR. The flavivirus NS1 protein:molecular and structural biology, immunology, role in pathogenesis and application as a diagnostic biomarker[J]. Antiviral Res, 2013, 98:192-208.
[5] Dighe SN, Dua K, Chellappan DK, et al. Recent update on anti-dengue drug discovery[J]. Eur J Med Chem, 2019, 176:431-455.
[6] Yauch LE, Shresta S. Dengue virus vaccine development[J]. Adv Virus Res, 2014, 88:315-372.
[7] Chen YL, Yin Z, Duraiswamy J, et al. Inhibition of dengue virus RNA synthesis by an adenosine nucleoside[J]. Antimicrob Agents Chemother, 2010, 54:2932-2939.
[8] Schul W, Liu W, Xu HY, et al. A dengue fever viremia model in mice shows reduction in viral replication and suppression of the inflammatory response after treatment with antiviral drugs[J]. J Infect Dis, 2007, 195:665-674.
[9] Yin Z, Chen YL, Schul W, et al. An adenosine nucleoside inhibitor of Dengue virus[J]. Proc Natl Acad Sci U S A, 2009, 106:20435-20439.
[10] Yin Z, Chen YL, Kondreddi RR, et al. N-Sulfonylanthranilic acid derivatives as allosteric inhibitors of Dengue viral RNA-dependent RNA polymerase[J]. J Med Chem, 2009, 52:7934-7937.
[11] Niyomrattanakit P, Chen YL, Dong H, et al. Inhibition of dengue virus polymerase by blocking of the RNA tunnel[J]. J Virol, 2010, 84:5678-5686.
[12] Yang CC, Hsieh YC, Lee SJ, et al. Novel dengue virus-specific NS2B/NS3 protease inhibitor, BP2109, discovered by a high-throughput screening assay[J]. Antimicrob Agents Chemother, 2011, 55:229-238.
[13] Lin C, Yu J, Hussain M, et al. Design, synthesis, and biological evaluation of novel 7-deazapurine nucleoside derivatives as potential anti-dengue virus agents[J]. Antiviral Res, 2018, 149:95-105.
[14] Migliaccio G, Tomassini JE, Carroll SS, et al. Characterization of resistance to non-obligate chain-terminating ribonucleoside analogs that inhibit hepatitis C virus replication in vitro[J]. J Biol Chem, 2003, 278:49164-49170.
[15] Olsen DB, Eldrup AB, Bartholomew L, et al. A 7-deaza-adenosine analog is a potent and selective inhibitor of hepatitis C virus replication with excellent pharmacokinetic properties[J]. Antimicrob Agents Chemother, 2004, 48:3944-3953.
[16] Chen YL, Yin Z, Lakshminarayana SB, et al. Inhibition of Dengue virus by an ester prodrug of an adenosine analog[J]. Antimicrob Agents Chemother, 2010, 54:3255-3261.
[17] Chen YL, Yokokawa F, Shi PY. The search for nucleoside/nucleotide analog inhibitors of Dengue virus[J]. Antiviral Res, 2015, 122:12-19.
[18] Timiri AK, Sinha BN, Jayaprakash V. Progress and prospects on DENV protease inhibitors[J]. Eur J Med Chem, 2016, 117:125-143.
[19] De Clercq E. Anti-HIV drugs:25 compounds approved within 25 years after the discovery of HIV[J]. Int J Antimicrob Agents, 2009, 33:307-320.
[20] Wyles DL. Antiviral resistance and the future landscape of hepatitis C virus infection therapy[J]. J Infect Dis, 2013, 207:S33-S39.
[21] Nitsche C, Behnam MA, Steuer C, et al. Retro peptide-hybrids as selective inhibitors of the Dengue virus NS2B-NS3 protease[J]. Antiviral Res, 2012, 94:72-79.
[22] Pambudi S, Kawashita N, Phanthanawiboon S, et al. A small compound targeting the interaction between nonstructural proteins 2B and 3 inhibits Dengue virus replication[J]. Biochem Biophys Res Commun, 2013, 440:393-398.
[23] Oliveira AS, Silva ML, Oliveira AF, et al. NS3 and NS5 proteins:important targets for anti-dengue drug design[J]. J Braz Chem Soc, 2014, 25:1759-1769.
[24] Byrd CM, Grosenbach DW, Berhanu A, et al. Novel benzoxazole inhibitor of Dengue virus replication that targets the NS3 helicase[J]. Antimicrob Agents Chemother, 2013, 57:1902-1912.
[25] Aguilera-Pesantes D,Robayo LE, Méndez PE, et al. Discovering key residues of Dengue virus NS2b-NS3-protease:new binding sites for antiviral inhibitors design[J]. Biochem Biophys Res Commun, 2017, 492:631-642.
[26] Leonel CA, Lima WG, Dos Santos M, et al. Pharmacophoric characteristics of Dengue virus NS2B/NS3pro inhibitors:a systematic review of the most promising compounds[J]. Arch Virol, 2018, 163:575-586.
[27] Lee JC, Chang FR, Chen SR, et al. Anti-dengue virus constituents from formosan zoanthid Palythoa mutuki[J]. Mar Drugs, 2016, 14:151.
[28] de Sousa LR, Wu H, Nebo L, et al. Flavonoids as noncompetitive inhibitors of Dengue virus NS2B-NS3 protease:inhibition kinetics and docking studies[J]. Bioorg Med Chem, 2015, 23:466-470.
[29] Li L, Basavannacharya C, Chan KW, et al. Structure-guided discovery of a novel non-peptide inhibitor of Dengue virus NS2B-NS3 protease[J]. Chem Biol Drug Des, 2015, 86:255-264.
[30] Miller S, Sparacio S, Bartenschlager R. Subcellular localization and membrane topology of the Dengue virus type 2 non-structural protein 4B[J]. J Biol Chem, 2006, 281:8854-8863.
[31] Xie X, Zou J, Wang QY, et al. Targeting dengue virus NS4B protein for drug discovery[J]. Antiviral Res, 2015, 118:39-45.
[32] Xie X, Wang QY, Xu HY, et al. Inhibition of dengue virus by targeting viral NS4B protein[J]. J Virol, 2011, 85:11183-11195.
[33] Alen MM, Schols D. Dengue virus entry as target for antiviral therapy[J]. J Trop Med, 2012, 2012:628475.
[34] De La Guardia C, Lleonart R. Progress in the identification of dengue virus entry/fusion inhibitors[J]. Biomed Res Int, 2014, 2014:825039.
[35] Hidari K, Abe T, Suzuki T. Carbohydrate-related inhibitors of dengue virus entry[J]. Viruses, 2013, 5:605-618.
[36] Costin JM, Jenwitheesuk E, Lok SM, et al. Structural optimization and de novo design of dengue virus entry inhibitory peptides[J]. PLoS Negl Trop Dis, 2010, 4:e721.
[37] Lok SM, Costin JM, Hrobowski YM, et al. Release of dengue virus genome induced by a peptide inhibitor[J]. PLoS One, 2012, 7:e50995.
[38] Modis Y, Ogata S, Clements D, et al. A ligand-binding pocket in the dengue virus envelope glycoprotein[J]. Proc Natl Acad Sci U S A, 2003, 100:6986-6991.
[39] Jadav SS, Kaptein S, Timiri A, et al. Design, synthesis, optimization and antiviral activity of a class of hybrid dengue virus E protein inhibitors[J]. Bioorg Med Chem Lett, 2015, 25:1747-1752.
[40] Behnam MA,Nitsche C, Boldescu V, et al. The medicinal chemistry of dengue virus[J]. J Med Chem, 2016, 59:5622-5649.
[41] Ma L, Jones CT, Groesch TD, et al. Solution structure of dengue virus capsid protein reveals another fold[J]. Proc Natl Acad Sci U S A, 2004, 101:3414-3419.
[42] Byrd CM, Dai D, Grosenbach DW, et al. A novel inhibitor of dengue virus replication that targets the capsid protein[J]. Antimicrob Agents Chemother, 2013, 57:15-25.
[43] Scaturro P, Trist IM, Paul D, et al. Characterization of the mode of action of a potent dengue virus capsid inhibitor[J]. J Virol, 2014, 88:11540-11555.
[44] Pastorino B, Nougairède A, Wurtz N, et al. Role of host cell factors in flavivirus infection:implications for pathogenesis and development of antiviral drugs[J]. Antiviral Res, 2010, 87:281-294.
[45] Rodenhuis-Zybert IA, Wilschut J, Smit JM. Dengue virus life cycle:viral and host factors modulating infectivity[J]. Cell Mol Life Sci, 2010, 67:2773-2786.
[46] Wang QY, Bushell S, Qing M, et al. Inhibition of Dengue virus through suppression of host pyrimidine biosynthesis[J]. J Virol, 2011, 85:6548-6556.
[47] Baltina LA, Tasi YT, Huang SH, et al. Glycyrrhizic acid derivatives as dengue virus inhibitors[J]. Bioorg Med Chem Lett, 2019, 29:126645.