X-ray Structural and Biological Evaluation of a Series of Potent and Highly Selective Inhibitors of Human Coronavirus Papain-like Proteases

详细信息    查看全文

• 作者：Yahira M. B谩ez-Santos ; Scott J. Barraza ; Michael W. Wilson ; Michael P. Agius ; Anna M. Mielech ; Nicole M. Davis ; Susan C. Baker ; Scott D. Larsen ; Andrew D. Mesecar
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：March 27, 2014
• 年：2014
• 卷：57
• 期：6
• 页码：2393-2412
• 全文大小：599K
• 年卷期：v.57,no.6(March 27, 2014)
• ISSN：1520-4804

文摘

Structure-guided design was used to generate a series of noncovalent inhibitors with nanomolar potency against the papain-like protease (PLpro) from the SARS coronavirus (CoV). A number of inhibitors exhibit antiviral activity against SARS-CoV infected Vero E6 cells and broadened specificity toward the homologous PLP2 enzyme from the human coronavirus NL63. Selectivity and cytotoxicity studies established a more than 100-fold preference for the coronaviral enzyme over homologous human deubiquitinating enzymes (DUBs), and no significant cytotoxicity in Vero E6 and HEK293 cell lines is observed. X-ray structural analyses of inhibitor-bound crystal structures revealed subtle differences between binding modes of the initial benzodioxolane lead (<b>15gb>) and the most potent analogues <b>3kb> and <b>3jb>, featuring a monofluoro substitution at para and meta positions of the benzyl ring, respectively. Finally, the less lipophilic bis(amide) <b>3eb> and methoxypyridine <b>5cb> exhibit significantly improved metabolic stability and are viable candidates for advancing to in vivo studies.