This article is a Preprint
Preprints are preliminary research reports that have not been certified by peer review. They should not be relied on to guide clinical practice or health-related behavior and should not be reported in news media as established information.
Preprints posted online allow authors to receive rapid feedback and the entire scientific community can appraise the work for themselves and respond appropriately. Those comments are posted alongside the preprints for anyone to read them and serve as a post publication assessment.
A comprehensive study of SARS-CoV-2 main protease (Mpro) inhibitor-resistant mutants selected in a VSV-based system (preprint)
biorxiv; 2023.
Preprint
in English
| bioRxiv | ID: ppzbmed-10.1101.2023.09.22.558628
ABSTRACT
Nirmatrelvir was the first protease inhibitor (PI) 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, and 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 PIs (nirmatrelvir and ensitrelvir) with cell-based and biochemical assays. Moreover, we showed the putative molecular mechanism of resistance based on in silico molecular modelling. These findings will help to understand SARS-CoV-2 protease-inhibitor-resistance mechanisms, the relevance of specific in the clinic and thereby inform treatment decisions.
Full text:
Available
Collection:
Preprints
Database:
bioRxiv
Main subject:
Vesicular Stomatitis
Language:
English
Year:
2023
Document Type:
Preprint
Similar
MEDLINE
...
LILACS
LIS