Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors.
Science
; 368(6489): 409-412, 2020 04 24.
Article
in English
| MEDLINE | ID: covidwho-164984
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 (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.
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Protease Inhibitors
/
Cysteine Endopeptidases
/
Viral Nonstructural Proteins
/
Betacoronavirus
/
Amides
Limits:
Animals
/
Humans
Language:
English
Journal:
Science
Year:
2020
Document Type:
Article
Affiliation country:
Science.abb3405
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