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DOI	10.1126/science.abb3405
	Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved a-ketoamide inhibitors
	Zhang L.; Lin D.; Sun X.; Curth U.; Drosten C.; Sauerhering L.; Becker S.; Rox K.; Hilgenfeld R.
发表日期	2020
ISSN	0036-8075
起始页码	409
结束页码	412
卷号	368 期号:6489
英文摘要	The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2) is a global health emergency. An attractive drug target among coronaviruses is the main protease (Mpro, also called 3CLpro) because of its essential role in processing the polyproteins that are translated from the viral RNA. We report the x-ray structures of the unliganded SARS-CoV-2 Mpro and its complex with an a-ketoamide inhibitor. This was derived from a previously designed inhibitor but with the P3-P2 amide bond incorporated into a pyridone ring to enhance the half-life of the compound in plasma. On the basis of the unliganded structure, we developed the lead compound into a potent inhibitor of the SARS-CoV-2 Mpro. The pharmacokinetic characterization of the optimized inhibitor reveals a pronounced lung tropism and suitability for administration by the inhalative route. © 2020 American Association for the Advancement of Science. All rights reserved.
关键词	alanine alpha ketoamide inhibitor antivirus agent isoleucine leucine proteinase Severe acute respiratory syndrome coronavirus 2 main protease threonine unclassified drug crystal structure drug enzyme enzyme activity inhibitor reaction kinetics amino acid sequence animal cell animal experiment animal tissue antiviral activity Article catalysis catalytic efficiency controlled study crystal structure dimerization dissociation constant drug clearance drug design drug distribution drug half life drug potency drug protein binding drug solubility drug structure EC50 enzyme inhibition human human cell hydrogen bond hydrophobicity IC50 maximum concentration mean residence time metabolic stability mouse nonhuman priority journal protein structure RNA replication SARS coronavirus Severe acute respiratory syndrome coronavirus 2 viral tropism virus inhibition Coronavirus SARS coronavirus
语种	英语
来源机构	Science
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/133552
推荐引用方式 GB/T 7714	Zhang L.,Lin D.,Sun X.,et al. Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved a-ketoamide inhibitors[J]. Science,2020,368(6489).
APA	Zhang L..,Lin D..,Sun X..,Curth U..,Drosten C..,...&Hilgenfeld R..(2020).Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved a-ketoamide inhibitors.,368(6489).
MLA	Zhang L.,et al."Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved a-ketoamide inhibitors".368.6489(2020).