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dc.contributor.authorDampalla, Chamandi S.
dc.contributor.authorRathnayake, Athri D.
dc.contributor.authorGalasiti Kankanamalage, Anushka C.
dc.contributor.authorKim, Yunjeong
dc.contributor.authorPerera, Krishani Dinali
dc.contributor.authorNguyen, Harry Nhat
dc.contributor.authorMiller, Matthew J.
dc.contributor.authorMadden, Trent K.
dc.contributor.authorPicard, Hunter R.
dc.contributor.authorThurman, Hayden A.
dc.contributor.authorKashipathy, Maithri M.
dc.contributor.authorLiu, Lijun
dc.contributor.authorBattaile, Kevin P.
dc.contributor.authorLovell, Scott
dc.contributor.authorChang, Kyeong-Ok
dc.contributor.authorGroutas, William C.
dc.identifier.citationDampalla, C. S., Rathnayake, A. D., Galasiti Kankanamalage, A. C., Kim, Y., Perera, K. D., Nguyen, H. N., . . . Groutas, W. C. (2022). Structure-Guided Design of Potent Spirocyclic Inhibitors of Severe Acute Respiratory Syndrome Coronavirus-2 3C-like Protease. Journal of Medicinal Chemistry, 65(11), 7818-7832.
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dc.description.abstractThe worldwide impact of the ongoing COVID-19 pandemic on public health has made imperative the discovery and development of direct-acting antivirals aimed at targeting viral and/or host targets. SARS-CoV-2 3C-like protease (3CLpro) has emerged as a validated target for the discovery of SARS-CoV-2 therapeutics because of the pivotal role it plays in viral replication. We describe herein the structure-guided design of highly potent inhibitors of SARS-CoV-2 3CLpro that incorporate in their structure novel spirocyclic design elements aimed at optimizing potency by accessing new chemical space. Inhibitors of both SARS-CoV-2 3CLpro and MERS-CoV 3CLpro that exhibit nM potency and high safety indices have been identified. The mechanism of action of the inhibitors and the structural determinants associated with binding were established using high-resolution cocrystal structures.
dc.publisherAmerican Chemical Society
dc.relation.ispartofseriesJournal of Medicinal Chemistry
dc.relation.ispartofseriesVolume 65, No. 11
dc.subjectChemical structure
dc.titleStructure-guided design of potent spirocyclic inhibitors of severe acute respiratory syndrome coronavirus-2 3C-like protease
dc.rights.holder© 2022 American Chemical Society

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