Activity profiling and crystal structures of inhibitor-bound SARS-CoV-2 papain-like protease: A framework for anti–COVID-19 drug design

Wioletta Rut, Zongyang Lv, Mikolaj Zmudzinski, Stephanie Patchett, Digant Nayak, Scott J. Snipas, Farid El Oualid, Tony T. Huang, Miklos Bekes, Marcin Drag, Shaun K. Olsen

Producción científica: Articlerevisión exhaustiva

272 Citas (Scopus)

Resumen

Viral papain-like cysteine protease (PLpro, NSP3) is essential for SARS-CoV-2 replication and represents a promising target for the development of antiviral drugs. Here, we used a combinatorial substrate library and performed comprehensive activity profiling of SARS-CoV-2 PLpro. On the scaffold of the best hits from positional scanning, we designed optimal fluorogenic substrates and irreversible inhibitors with a high degree of selectivity for SARS PLpro. We determined crystal structures of two of these inhibitors in complex with SARS-CoV-2 PLpro that reveals their inhibitory mechanisms and provides a molecular basis for the observed substrate specificity profiles. Last, we demonstrate that SARS-CoV-2 PLpro harbors deISGylating activity similar to SARSCoV-1 PLpro but its ability to hydrolyze K48-linked Ub chains is diminished, which our sequence and structure analysis provides a basis for. Together, this work has revealed the molecular rules governing PLpro substrate specificity and provides a framework for development of inhibitors with potential therapeutic value or drug repurposing.

Idioma originalEnglish (US)
Número de artículoeabd4596
PublicaciónScience Advances
Volumen6
N.º42
DOI
EstadoPublished - oct 2020

ASJC Scopus subject areas

  • General

Huella

Profundice en los temas de investigación de 'Activity profiling and crystal structures of inhibitor-bound SARS-CoV-2 papain-like protease: A framework for anti–COVID-19 drug design'. En conjunto forman una huella única.

Citar esto