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

doi:10.1021/acs.jmedchem.9b01828

	alpha-Ketoamides as Broad-Spectrum Inhibitors of Coronavirus and Enterovirus Replication: Structure-Based Design, Synthesis, and Activity Assessment
	Zhang, Linlin 3,4; Lin, Daizong 2,3,4; Kusov, Yuri 3; Nian, Yong 2; Ma, Qingjun 3; Wang, Jiang 2; von Brunn, Albrecht 5; Leyssen, Pieter 1; Lanko, Kristina 1; Neyts, Johan 1
刊名	JOURNAL OF MEDICINAL CHEMISTRY
	2020-05-14
卷号	63 期号:9 页码:4562-4578
ISSN号	0022-2623
DOI	10.1021/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.
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关键词	MAIN PROTEINASE ; 3C PROTEASE ; 3C-LIKE PROTEASES ; POTENT INHIBITION ; CYCLOSPORINE-A ; MOUTH-DISEASE ; M-PRO ; SARS ; VIRUS ; HAND
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000535279800012
内容类型	期刊论文
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.Univ Leuven, Rega Inst Med Res, B-3000 Leuven, Belgium 2.Shanghai Inst Mat Med, Shanghai 201203, Peoples R China 3.Univ Lubeck, Inst Biochem, Ctr Struct & Cell Biol Med, D-23562 Lubeck, Germany 4.Univ Lubeck, German Ctr Infect Res DZIF, Hamburg Lubeck Borstel Riems Site, D-23562 Lubeck, Germany 5.Ludwig Maximilians Univ Munchen, Max von Pettenkofer Inst, D-80336 Munich, Germany 6.Leiden Univ, Med Ctr, NL-2333 ZA Leiden, Netherlands
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.