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alpha-Ketoamides as Broad-Spectrum Inhibitors of Coronavirus and Enterovirus Replication: Structure-Based Design, Synthesis, and Activity Assessment

文献类型：期刊论文

作者Zhang, Linlin4,5; Lin, Daizong3,4,5; Kusov, Yuri4; Nian, Yong3; Ma, Qingjun4; Wang, Jiang3; von Brunn, Albrecht1; Leyssen, Pieter6; Lanko, Kristina6; Neyts, Johan6
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2020-05-14
卷号63期号:9页码:4562-4578
ISSN号0022-2623
DOI10.1021/acs.jmedchem.9b01828
通讯作者Liu, Hong(hliu@simm.ac.cn) ; Hilgenfeld, Rolf(hilgenfeld@biochem.uni-luebeck.de)
英文摘要The main protease of coronaviruses and the 3C protease of enteroviruses share a similar active-site architecture and a unique requirement for glutamine in the P1 position of the substrate. Because of their unique specificity and essential role in viral polyprotein processing, these proteases are suitable targets for the development of antiviral drugs. In order to obtain near-equipotent, broad-spectrum antivirals against alphacoronaviruses, betacoronaviruses, and enteroviruses, we pursued a structure-based design of peptidomimetic alpha-ketoamides as inhibitors of main and 3C proteases. Six crystal structures of protease-inhibitor complexes were determined as part of this study. Compounds synthesized were tested against the recombinant proteases as well as in viral replicons and virus-infected cell cultures; most of them were not cell-toxic. Optimization of the P2 substituent of the alpha-ketoamides proved crucial for achieving near-equipotency against the three virus genera. The best near-equipotent inhibitors, 11u (P2 = cyclopentylmethyl) and 11r (P2 = cyclo-hexylmethyl), display low-micromolar EC50 values against enteroviruses, alphacoronaviruses, and betacoronaviruses in cell cultures. In Huh7 cells, 11r exhibits three-digit picomolar activity against the Middle East Respiratory Syndrome coronavirus.
WOS关键词MAIN PROTEINASE ; 3C PROTEASE ; 3C-LIKE PROTEASES ; POTENT INHIBITION ; CYCLOSPORINE-A ; MOUTH-DISEASE ; M-PRO ; SARS ; VIRUS ; HAND
资助项目European Commission through its SILVER project[HEALTH-F3-2010-260644] ; German Center for Infection Research (DZIF)[TTU 01.803] ; Natural Science Foundation of China[81620108027]
WOS研究方向Pharmacology & Pharmacy
语种英语
出版者AMER CHEMICAL SOC
WOS记录号WOS:000535279800012
源URL[http://119.78.100.183/handle/2S10ELR8/280131]  
专题中国科学院上海药物研究所
通讯作者Liu, Hong; Hilgenfeld, Rolf
作者单位1.Ludwig Maximilians Univ Munchen, Max von Pettenkofer Inst, D-80336 Munich, Germany
2.Leiden Univ, Med Ctr, NL-2333 ZA Leiden, Netherlands
3.Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
4.Univ Lubeck, Inst Biochem, Ctr Struct & Cell Biol Med, D-23562 Lubeck, Germany
5.Univ Lubeck, German Ctr Infect Res DZIF, Hamburg Lubeck Borstel Riems Site, D-23562 Lubeck, Germany
6.Univ Leuven, Rega Inst Med Res, B-3000 Leuven, Belgium
推荐引用方式
GB/T 7714		 Zhang, Linlin,Lin, Daizong,Kusov, Yuri,et al. alpha-Ketoamides as Broad-Spectrum Inhibitors of Coronavirus and Enterovirus Replication: Structure-Based Design, Synthesis, and Activity Assessment[J]. JOURNAL OF MEDICINAL CHEMISTRY,2020,63(9):4562-4578.
APA Zhang, Linlin.,Lin, Daizong.,Kusov, Yuri.,Nian, Yong.,Ma, Qingjun.,...&Hilgenfeld, Rolf.(2020).alpha-Ketoamides as Broad-Spectrum Inhibitors of Coronavirus and Enterovirus Replication: Structure-Based Design, Synthesis, and Activity Assessment.JOURNAL OF MEDICINAL CHEMISTRY,63(9),4562-4578.
MLA Zhang, Linlin,et al."alpha-Ketoamides as Broad-Spectrum Inhibitors of Coronavirus and Enterovirus Replication: Structure-Based Design, Synthesis, and Activity Assessment".JOURNAL OF MEDICINAL CHEMISTRY 63.9(2020):4562-4578.

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来源：上海药物研究所

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