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
en En
| MEDLINE
| ID: mdl-32198291
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.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Inhibidores de Proteasas
/
Cisteína Endopeptidasas
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Proteínas no Estructurales Virales
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Betacoronavirus
/
Amidas
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Science
Año:
2020
Tipo del documento:
Article
País de afiliación:
Alemania