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dc.contributor.authorFrieman, M.
dc.contributor.authorMatthews, K.
dc.contributor.authorTaylor, J.
dc.contributor.authorJones, G.
dc.date.accessioned2020-03-27T15:13:17Z
dc.date.available2020-03-27T15:13:17Z
dc.date.issued2011
dc.identifier.urihttps://www.scopus.com/inward/record.uri?eid=2-s2.0-82555170562&doi=10.1371%2fjournal.pone.0028479&partnerID=40&md5=b602e74132d43651bb340f52ee1a854b
dc.identifier.urihttp://hdl.handle.net/10713/12425
dc.description.abstractSevere 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.en_US
dc.description.urihttps://doi.org/10.1371/journal.pone.0028479en_US
dc.language.isoen_USen_US
dc.relation.ispartofPLoS ONE
dc.subjectsevere acute respiratory coronavirusen_US
dc.subjectSARS-CoVen_US
dc.subjectyeast-based assayen_US
dc.subjectinhibitorsen_US
dc.subject.meshSARS Virusen_US
dc.subject.meshYeastsen_US
dc.titleYeast based small molecule screen for inhibitors of SARS-CoVen_US
dc.typeArticleen_US
dc.identifier.doi10.1371/journal.pone.0028479
dc.identifier.pmid22164298
dc.identifier.ispublishedNo


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