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- Title
SARS-CoV-2 3CL<sup>pro</sup> mutations selected in a VSV-based system confer resistance to nirmatrelvir, ensitrelvir, and GC376.
- Authors
Heilmann, Emmanuel; Costacurta, Francesco; Moghadasi, Seyed Arad; Ye, Chengjin; Pavan, Matteo; Bassani, Davide; Volland, Andre; Ascher, Claudia; Weiss, Alexander Kurt Hermann; Bante, David; Harris, Reuben S.; Moro, Stefano; Rupp, Bernhard; Martinez-Sobrido, Luis; von Laer, Dorothee
- Abstract
Protease inhibitors are among the most powerful antiviral drugs. Nirmatrelvir is the first protease inhibitor specifically developed against the SARS-CoV-2 protease 3CLpro that has been licensed for clinical use. To identify mutations that confer resistance to this protease inhibitor, we engineered a chimeric vesicular stomatitis virus (VSV) that expressed a polyprotein composed of the VSV glycoprotein (G), the SARS-CoV-2 3CLpro, and the VSV polymerase (L). Viral replication was thus dependent on the autocatalytic processing of this precursor protein by 3CLpro and release of the functional viral proteins G and L, and replication of this chimeric VSV was effectively inhibited by nirmatrelvir. Using this system, we applied nirmatrelvir to select for resistance mutations. Resistance was confirmed by retesting nirmatrelvir against the selected mutations in additional VSV-based systems, in an independently developed cellular system, in a biochemical assay, and in a recombinant SARS-CoV-2 system. We demonstrate that some mutants are cross-resistant to ensitrelvir and GC376, whereas others are less resistant to these compounds. Furthermore, we found that most of these resistance mutations already existed in SARS-CoV-2 sequences that have been deposited in the NCBI and GISAID databases, indicating that these mutations were present in circulating SARS-CoV-2 strains. Assessing antiviral activity: Nirmatrelvir, ensitrelvir, and GC376 are SARS-CoV-2 3CLpro inhibitors that provide a promising strategy for treating individuals with COVID-19. However, as antivirals become more widely used, SARS-CoV-2 may develop mutations that confer resistance against these antivirals. Here, Heilmann et al. developed a vesicular stomatitis virus (VSV)–based system, where the SARS-CoV-23CLpro was essential for replication of VSV. The authors used this system to select for nirmaltrelvir resistance mutations, identifying several. Some of the mutations were specific to nirmaltrelvir, whereas others conferred resistance to additional 3CLpro inhibitors. The authors validated the identified resistance-conferring mutations using multiple other strategies, suggesting that this VSV-based system could be used to further understand SARS-CoV-2 antiviral resistance. —CM
- Subjects
SARS-CoV-2; VESICULAR stomatitis; PROTEIN precursors; VIRAL proteins; G proteins
- Publication
Science Translational Medicine, 2023, Vol 15, Issue 678, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.abq7360