Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease.
basic_science · Level V
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- Record sourced from PubMed, PMID 32321856.
- Also identified by DOI 10.1126/science.abb4489 and PMC identifier 7179937.
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Abstract
SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is the etiological agent responsible for the global COVID-19 (coronavirus disease 2019) outbreak. The main protease of SARS-CoV-2, M<sup>pro</sup>, is a key enzyme that plays a pivotal role in mediating viral replication and transcription. We designed and synthesized two lead compounds (<b>11a</b> and <b>11b</b>) targeting M<sup>pro</sup> Both exhibited excellent inhibitory activity and potent anti-SARS-CoV-2 infection activity. The x-ray crystal structures of SARS-CoV-2 M<sup>pro</sup> in complex with <b>11a</b> or <b>11b</b>, both determined at a resolution of 1.5 angstroms, showed that the aldehyde groups of <b>11a</b> and <b>11b</b> are covalently bound to cysteine 145 of M<sup>pro</sup> Both compounds showed good pharmacokinetic properties in vivo, and <b>11a</b> also exhibited low toxicity, which suggests that these compounds are promising drug candidates.
Medical subject headings
- Antiviral Agents
- Betacoronavirus
- Drug Design
- Viral Nonstructural Proteins