Abstract
Severe acute respiratory coronavirus (SARS-CoV) emerged in 2002, resulting in roughly 8000 cases worldwide and 10% mortality. The animal reservoirs for SARS-CoV precursors still exist and the likelihood of future outbreaks in the human population is high. The SARS-CoV papain-like protease (PLP) is an attractive target for pharmaceutical development because it is essential for virus replication and is conserved among human coronaviruses. A yeast-based assay was established for PLP activity that relies on the ability of PLP to induce a pronounced slow-growth phenotype when expressed in S. cerevisiae. Induction of the slow-growth phenotype was shown to take place over a 60-hour time course, providing the basis for conducting a screen for small molecules that restore growth by inhibiting the function of PLP. Five chemical suppressors of the slow-growth phenotype were identified from the 2000 member NIH Diversity Set library. One of these, NSC158362, potently inhibited SARS-CoV replication in cell culture without toxic effects on cells, and it specifically inhibited SARS-CoV replication but not influenza virus replication. The effect of NSC158362 on PLP protease, deubiquitinase and anti-interferon activities was investigated but the compound did not alter these activities. Another suppressor, NSC158011, demonstrated the ability to inhibit PLP protease activity in a cell-based assay. The identification of these inhibitors demonstrated a strong functional connection between the PLP-based yeast assay, the inhibitory compounds, and SARS-CoV biology. Furthermore the data with NSC158362 suggest a novel mechanism for inhibition of SARS-CoV replication that may involve an unknown activity of PLP, or alternatively a direct effect on a cellular target that modifies or bypasses PLP function in yeast and mammalian cells. Copyright 2011 Frieman et al.Identifier to cite or link to this item
https://www.scopus.com/inward/record.uri?eid=2-s2.0-82555170562&doi=10.1371%2fjournal.pone.0028479&partnerID=40&md5=b602e74132d43651bb340f52ee1a854b; http://hdl.handle.net/10713/12425ae974a485f413a2113503eed53cd6c53
10.1371/journal.pone.0028479
Scopus Count
Collections
Related articles
- The papain-like protease determines a virulence trait that varies among members of the SARS-coronavirus species.
- Authors: Niemeyer D, Mösbauer K, Klein EM, Sieberg A, Mettelman RC, Mielech AM, Dijkman R, Baker SC, Drosten C, Müller MA
- Issue date: 2018 Sep
- High-throughput assay using a GFP-expressing replicon for SARS-CoV drug discovery.
- Authors: Ge F, Xiong S, Lin FS, Zhang ZP, Zhang XE
- Issue date: 2008 Nov
- The SARS-coronavirus papain-like protease: structure, function and inhibition by designed antiviral compounds.
- Authors: Báez-Santos YM, St John SE, Mesecar AD
- Issue date: 2015 Mar
- 3C-like protease inhibitors block coronavirus replication in vitro and improve survival in MERS-CoV-infected mice.
- Authors: Rathnayake AD, Zheng J, Kim Y, Perera KD, Mackin S, Meyerholz DK, Kashipathy MM, Battaile KP, Lovell S, Perlman S, Groutas WC, Chang KO
- Issue date: 2020 Aug 19
- Identification of novel small-molecule inhibitors of severe acute respiratory syndrome-associated coronavirus by chemical genetics.
- Authors: Kao RY, Tsui WH, Lee TS, Tanner JA, Watt RM, Huang JD, Hu L, Chen G, Chen Z, Zhang L, He T, Chan KH, Tse H, To AP, Ng LW, Wong BC, Tsoi HW, Yang D, Ho DD, Yuen KY
- Issue date: 2004 Sep