Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors
By Linlin Zhang, Daizong Lin, Xinyuanyuan Sun, U. Curth, Christian Drosten, Lucie Sauerhering, S. Becker, K. Rox, Rolf Hilgenfeld. Science, 2020
2,780 citations recorded by the source corpus.
Targeting a key enzyme in SARS-CoV-2 Scientists across the world are working to understand severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19). Zhang et al. determined the x-ray crystal structure of a key protein in the virus' life cycle: the main protease. This enzyme cuts the polyproteins translated from viral RNA to yield functional viral proteins. The authors also developed a lead compound into a potent inhibitor and obtained a structure with the inhibitor bound, work that may provide a basis for development of anticoronaviral drugs. Science, this issue p. 409 Optimized inhibitor of a key enzyme of the novel coronavirus exhibits pronounced lung tropism. The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2) is a global health emergency. An attractive drug target among coronaviruses is the main protease (Mpro, also called 3CLpro) because of its essential role in processing the polyproteins that are translated from the viral RNA. We report the x-ray structures of the unliganded SARS-CoV-2 Mpro and its complex with an α-ketoamide inhibitor. This was derived from a previously designed inhibitor but with the P3-P2 amide bond incorporated into a pyridone ring to enhance the half-life of the compound in plasma. On the basis of the unliganded structure, we developed the lead compound into a potent inhibitor of the SARS-CoV-2 Mpro. The pharmacokinetic characterization of the optimized inhibitor reveals a pronounced lung tropism and suitability for administration by the inhalative route.
Subfields: Computational Theory and Mathematics, Infectious Diseases, Materials Chemistry
View Paper: https://www.semanticscholar.org/paper/fe378a510b608779e06e6d6227d4bf3c40fbb685
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Citations in the corpus
- Insights into SARS-CoV-2 genome, structure, evolution, pathogenesis and therapies: Structural genomics approach (2020, neutral): “53 Å for all Cα atoms by comparing their published structures [77,78].”
- The SARS-CoV-2 main protease as drug target (2020, neutral): “The first reported inhibitors were covalently binding peptidomimetics (1–3) addressing the major substrate-recognition motif from P1′ to P3.”
- The rise of artificial intelligence in healthcare applications (2020, methodology): “This is combined with other efforts to employ DL to find molecules that can interact with the main proteases (M pro or 3CL pro ) of the virus, resulting in the disruption of the replication machinery of the virus inside the host [67,68].”
- Papain-like protease regulates SARS-CoV-2 viral spread and innate immunity (2020, neutral): “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 .”
- Fast Identification of Possible Drug Treatment of Coronavirus Disease −19 (COVID-19) Through Computational Drug Repurposing Study (2020, methodology): “25 Two types of HVS filters were employed: Glide 7 flexible docking followed by MM-PBSA-WSAS.”