Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease
By Wenhao Dai, Bing Zhang, Xiaming Jiang, H. Su, Jian Li, Yao Zhao, Xiong Xie, Zhenming Jin, Jingjing Peng, Fengjiang Liu and 17 more. Science, 2020
1,280 citations recorded by the source corpus.
Promising antiviral protease inhibitors With no vaccine or proven effective drug against the virus that causes coronavirus disease 2019 (COVID-19), scientists are racing to find clinical antiviral treatments. A promising drug target is the viral main protease Mpro, which plays a key role in viral replication and transcription. Dai et al. designed two inhibitors, 11a and 11b, based on analyzing the structure of the Mpro active site. Both strongly inhibited the activity of Mpro and showed good antiviral activity in cell culture. Compound 11a had better pharmacokinetic properties and low toxicity when tested in mice and dogs, suggesting that this compound is a promising drug candidate. Science, this issue p. 1331 Two peptidomimetic aldehydes were designed, synthesized, and evaluated as antiviral drug candidates. 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, Mpro, is a key enzyme that plays a pivotal role in mediating viral replication and transcription. We designed and synthesized two lead compounds (11a and 11b) targeting Mpro. Both exhibited excellent inhibitory activity and potent anti–SARS-CoV-2 infection activity. The x-ray crystal structures of SARS-CoV-2 Mpro in complex with 11a or 11b, both determined at a resolution of 1.5 angstroms, showed that the aldehyde groups of 11a and 11b are covalently bound to cysteine 145 of Mpro. Both compounds showed good pharmacokinetic properties in vivo, and 11a also exhibited low toxicity, which suggests that these compounds are promising drug candidates.
Subfields: Computational Theory and Mathematics, Infectious Diseases
View Paper: https://www.semanticscholar.org/paper/ca9f24c7a44f260543756ce7960c0a9b9f30d747
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In Computational Theory and Mathematics
Citations in the corpus
- Boceprevir, GC-376, and calpain inhibitors II, XII inhibit SARS-CoV-2 viral replication by targeting the viral main protease (2020, methodology): “S5a).(11) In protomer C, however, the same hydroxide group orients outwards from the oxyanion hole, forming hydrogen bonds with His41 (Fig.”
- The SARS-CoV-2 main protease as drug target (2020, neutral): “6c).(91) Similar peptide-aldehydes have previously been explored as inhibitors of SARSCoV Mpro.”
- Papain-like protease regulates SARS-CoV-2 viral spread and innate immunity (2020, positive): “Furthermore, the main protease of SARS-CoV-2 has been in focus as a potential drug target against COVID-19 and several novel inhibitors have already been described 38–40 .”