Your browser doesn't support javascript.
loading
A comprehensive study of SARS-CoV-2 main protease (Mpro) inhibitor-resistant mutants selected in a VSV-based system.
Costacurta, Francesco; Dodaro, Andrea; Bante, David; Schöppe, Helge; Peng, Ju-Yi; Sprenger, Bernhard; He, Xi; Moghadasi, Seyed Arad; Egger, Lisa Maria; Fleischmann, Jakob; Pavan, Matteo; Bassani, Davide; Menin, Silvia; Rauch, Stefanie; Krismer, Laura; Sauerwein, Anna; Heberle, Anne; Rabensteiner, Toni; Ho, Joses; Harris, Reuben S; Stefan, Eduard; Schneider, Rainer; Dunzendorfer-Matt, Theresia; Naschberger, Andreas; Wang, Dai; Kaserer, Teresa; Moro, Stefano; von Laer, Dorothee; Heilmann, Emmanuel.
Afiliación
  • Costacurta F; Institute of Virology, Medical University of Innsbruck, Innsbruck, Tyrol, Austria.
  • Dodaro A; Molecular Modeling Section (MMS), Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padova, Italy.
  • Bante D; Institute of Virology, Medical University of Innsbruck, Innsbruck, Tyrol, Austria.
  • Schöppe H; Institute of Pharmacy/Pharmaceutical Chemistry and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innsbruck, Tyrol, Austria.
  • Peng JY; Department of Infectious Diseases and Vaccines Research, MRL, Merck & Co., Inc., Rahway, New Jersey, United States of America.
  • Sprenger B; Institute of Biochemistry and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innsbruck, Austria.
  • He X; Department of Infectious Diseases and Vaccines Research, MRL, Merck & Co., Inc., Rahway, New Jersey, United States of America.
  • Moghadasi SA; Department of Biochemistry, Molecular Biology and Biophysics, Institute for Molecular Virology, University of Minnesota, Minneapolis, Minnesota, United States of America.
  • Egger LM; Institute of Molecular Biochemistry, Biocentre, Medical University of Innsbruck, Innsbruck, Austria.
  • Fleischmann J; Institute of Molecular Biology, University of Innsbruck, Innsbruck, Tyrol, Austria.
  • Pavan M; Tyrolean Cancer Research Institute (TKFI), Innsbruck, Tyrol, Austria.
  • Bassani D; Molecular Modeling Section (MMS), Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padova, Italy.
  • Menin S; Molecular Modeling Section (MMS), Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padova, Italy.
  • Rauch S; Molecular Modeling Section (MMS), Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padova, Italy.
  • Krismer L; Institute of Virology, Medical University of Innsbruck, Innsbruck, Tyrol, Austria.
  • Sauerwein A; Institute of Virology, Medical University of Innsbruck, Innsbruck, Tyrol, Austria.
  • Heberle A; Institute of Virology, Medical University of Innsbruck, Innsbruck, Tyrol, Austria.
  • Rabensteiner T; Institute of Virology, Medical University of Innsbruck, Innsbruck, Tyrol, Austria.
  • Ho J; Institute of Virology, Medical University of Innsbruck, Innsbruck, Tyrol, Austria.
  • Harris RS; Bioinformatics Institute, Agency for Science Technology and Research, Singapore, Singapore.
  • Stefan E; Department of Biochemistry and Structural Biology, University of Texas Health San Antonio, San Antonio, Texas, United States of America.
  • Schneider R; Howard Hughes Medical Institute, University of Texas Health San Antonio, San Antonio, Texas, United States of America.
  • Dunzendorfer-Matt T; Institute of Molecular Biology, University of Innsbruck, Innsbruck, Tyrol, Austria.
  • Naschberger A; Tyrolean Cancer Research Institute (TKFI), Innsbruck, Tyrol, Austria.
  • Wang D; Institute of Biochemistry and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innsbruck, Austria.
  • Kaserer T; Institute of Molecular Biochemistry, Biocentre, Medical University of Innsbruck, Innsbruck, Austria.
  • Moro S; Division of Biological and Environmental Sciences and Engineering (BESE), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia.
  • von Laer D; Department of Infectious Diseases and Vaccines Research, MRL, Merck & Co., Inc., Rahway, New Jersey, United States of America.
  • Heilmann E; Institute of Pharmacy/Pharmaceutical Chemistry and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innsbruck, Tyrol, Austria.
PLoS Pathog ; 20(9): e1012522, 2024 Sep.
Article en En | MEDLINE | ID: mdl-39259728
ABSTRACT
Nirmatrelvir was the first protease inhibitor specifically developed against the SARS-CoV-2 main protease (3CLpro/Mpro) and licensed for clinical use. As SARS-CoV-2 continues to spread, variants resistant to nirmatrelvir and other currently available treatments are likely to arise. This study aimed to identify and characterize mutations that confer resistance to nirmatrelvir. To safely generate Mpro resistance mutations, we passaged a previously developed, chimeric vesicular stomatitis virus (VSV-Mpro) with increasing, yet suboptimal concentrations of nirmatrelvir. Using Wuhan-1 and Omicron Mpro variants, we selected a large set of mutants. Some mutations are frequently present in GISAID, suggesting their relevance in SARS-CoV-2. The resistance phenotype of a subset of mutations was characterized against clinically available protease inhibitors (nirmatrelvir and ensitrelvir) with cell-based, biochemical and SARS-CoV-2 replicon assays. Moreover, we showed the putative molecular mechanism of resistance based on in silico molecular modelling. These findings have implications on the development of future generation Mpro inhibitors, will help to understand SARS-CoV-2 protease inhibitor resistance mechanisms and show the relevance of specific mutations, thereby informing treatment decisions.
Asunto(s)
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Antivirales / Inhibidores de Proteasas / Farmacorresistencia Viral / Proteasas 3C de Coronavirus / SARS-CoV-2 / Mutación Límite: Animals / Humans Idioma: En Revista: PLoS Pathog Año: 2024 Tipo del documento: Article País de afiliación: Austria Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Antivirales / Inhibidores de Proteasas / Farmacorresistencia Viral / Proteasas 3C de Coronavirus / SARS-CoV-2 / Mutación Límite: Animals / Humans Idioma: En Revista: PLoS Pathog Año: 2024 Tipo del documento: Article País de afiliación: Austria Pais de publicación: Estados Unidos