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


ABSTRACT: 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 IC(50) value of 20 microM, which was improved to 600 nM via synthetic optimization. The resulting compound, GRL0617, inhibited SARS-CoV viral replication in Vero E6 cells with an EC(50) of 15 microM 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.

SUBMITTER: Ratia K 

PROVIDER: S-EPMC2571001 | biostudies-literature | 2008 Oct

REPOSITORIES: biostudies-literature

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

Ratia Kiira K   Pegan Scott S   Takayama Jun J   Sleeman Katrina K   Coughlin Melissa M   Baliji Surendranath S   Chaudhuri Rima R   Fu Wentao W   Prabhakar Bellur S BS   Johnson Michael E ME   Baker Susan C SC   Ghosh Arun K AK   Mesecar Andrew D AD  

Proceedings of the National Academy of Sciences of the United States of America 20081013 42


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  ...[more]

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