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A noncovalent class of papain-like protease/deubiquitinase inhibitors blocks SARS virus replication.
Proc Natl Acad Sci U S A. 2008 Oct 21; 105(42):16119-24.PN

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.

Authors+Show Affiliations

Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois, Chicago, IL 60607, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

18852458

Citation

Ratia, Kiira, et al. "A Noncovalent Class of Papain-like Protease/deubiquitinase Inhibitors Blocks SARS Virus Replication." Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 42, 2008, pp. 16119-24.
Ratia K, Pegan S, Takayama J, et al. A noncovalent class of papain-like protease/deubiquitinase inhibitors blocks SARS virus replication. Proc Natl Acad Sci USA. 2008;105(42):16119-24.
Ratia, K., Pegan, S., Takayama, J., Sleeman, K., Coughlin, M., Baliji, S., Chaudhuri, R., Fu, W., Prabhakar, B. S., Johnson, M. E., Baker, S. C., Ghosh, A. K., & Mesecar, A. D. (2008). A noncovalent class of papain-like protease/deubiquitinase inhibitors blocks SARS virus replication. Proceedings of the National Academy of Sciences of the United States of America, 105(42), 16119-24. https://doi.org/10.1073/pnas.0805240105
Ratia K, et al. A Noncovalent Class of Papain-like Protease/deubiquitinase Inhibitors Blocks SARS Virus Replication. Proc Natl Acad Sci USA. 2008 Oct 21;105(42):16119-24. PubMed PMID: 18852458.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A noncovalent class of papain-like protease/deubiquitinase inhibitors blocks SARS virus replication. AU - Ratia,Kiira, AU - Pegan,Scott, AU - Takayama,Jun, AU - Sleeman,Katrina, AU - Coughlin,Melissa, AU - Baliji,Surendranath, AU - Chaudhuri,Rima, AU - Fu,Wentao, AU - Prabhakar,Bellur S, AU - Johnson,Michael E, AU - Baker,Susan C, AU - Ghosh,Arun K, AU - Mesecar,Andrew D, Y1 - 2008/10/13/ PY - 2008/10/15/pubmed PY - 2008/11/19/medline PY - 2008/10/15/entrez SP - 16119 EP - 24 JF - Proceedings of the National Academy of Sciences of the United States of America JO - Proc. Natl. Acad. Sci. U.S.A. VL - 105 IS - 42 N2 - 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. SN - 1091-6490 UR - https://www.unboundmedicine.com/medline/citation/18852458/A_noncovalent_class_of_papain_like_protease/deubiquitinase_inhibitors_blocks_SARS_virus_replication_ L2 - http://www.pnas.org/cgi/pmidlookup?view=long&pmid=18852458 DB - PRIME DP - Unbound Medicine ER -