A noncovalent class of papain-like protease/deubiquitinase inhibitors blocks SARS virus replication

作者：Ratia Kiira; Pegan Scott; Takayama Jun; Sleeman Katrina; Coughlin Melissa; Baliji Surendranath; Chaudhuri Rima; Fu Wentao; Prabhakar Bellur S; Johnson Michael E; Baker Susan C; Ghosh Arun K^*; Mesecar Andrew D

来源：Proceedings of the National Academy of Sciences, 2008, 105(42): 16119-16124.

DOI：10.1073/pnas.0805240105

• ubiquitin-specific protease
• noncovalent cysteine protease inhibitor
• severe acute respiratory syndrome antiviral
• X-ray structure

We report the discovery and optimization of a potent inhibitor against the papain-like protease (PLpro) from the coronavirus that causes severe acute respiratory syndrome (SARS-CoV). This unique protease is not only responsible for processing the viral polyprotein into its functional units but is also capable of cleaving ubiquitin and ISG15 conjugates and plays a significant role in helping SARS-CoV evade the human immune system. We screened a structurally diverse library of 50,080 compounds for inhibitors of PLpro and discovered a noncovalent lead inhibitor with an IC50 value of 20 mu M, which was improved to 600 nM via synthetic optimization. The resulting compound, GRL0617, inhibited SARS-CoV viral replication in Vero E6 cells with an EC50 of 15 mu M and had no associated cytotoxicity. The X-ray structure of PLpro in complex with GRL0617 indicates that the compound has a unique mode of inhibition whereby it binds within the S4-S3 subsites of the enzyme and induces a loop closure that shuts down catalysis at the active site. These findings provide proof-of -principle that PLpro is a viable target for development of antivirals directed against SARS-CoV, and that potent noncovalent cysteine protease inhibitors can be developed with specificity directed toward pathogenic deubiquitinating enzymes without inhibiting host DUBS.

• 出版日期2008-10-21