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Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors
Abstract
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 (M pro , also called 3CL pro ) 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 M pro 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 M pro . The pharmacokinetic characterization of the optimized inhibitor reveals a pronounced lung tropism and suitability for administration by the inhalative route.
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DL is being employed to find molecules that interact with the main proteases (Mpro or 3CLpro) of the virus, disrupting the replication machinery of the virus inside the host.
“This is combined with other efforts to employ DL to find molecules that can interact with the main proteases (Mpro or 3CLpro) of the virus, resulting in the disruption of the replication machinery of the virus inside the host [67], [68].”
From The rise of artificial intelligence in healthcare applications (2020) · cites this paper as [68]
The paper’s main text (indexed under Abstract; page unavailable) identifies Mpro as 3CLpro and reports that an α-ketoamide inhibitor suppresses SARS-CoV-2 replication in infected human cells. It describes crystal-structure-guided docking and inhibitor development, but does not report using deep learning to find molecules; that central part of the attributed claim is unsupported. (LLM, conf=0.88)
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Metadata
- Authors
- Zhang, L., Lin, D., Sun, X., Curth, U., Drosten, C., Sauerhering, L., Becker, S., Rox, K., & Hilgenfeld, R.
- Affiliations
- Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck, 23562 Lübeck, Germany.
- Institute for Biophysical Chemistry, Hannover Medical School, 30625 Hannover, Germany.
- Institute of Virology, Charité Universitätsmedizin Berlin, 10117 Berlin, Germany.
- Institute of Virology, University of Marburg, 35043 Marburg, Germany.
- Department of Chemical Biology, Helmholtz Center for Infection Research (HZI), 38124 Braunschweig, Germany.
- ORCID
- Venue
- Science
- Published
- 2020-04-24
- Volume
- 368
- Issue
- 6489
- Pages
- 409-412
- ISSN
- 0036-8075
- 1095-9203
- PMC
- PMC7164518
- Cited by
- 2,895
- References
- 4
- Language
- en
- Funders
- German Center for Infection Research (TTU01 / 8011801806, TTU09 / 8004709710)
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