Strategy to overcome a nirmatrelvir resistance mechanism in the SARS-CoV-2 nsp5 protease.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 40479048.
- Also identified by DOI 10.1126/sciadv.adv8875 and PMC identifier 12143351.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
E166V in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nsp5 protease confers strong resistance to the antiviral component of Paxlovid, nirmatrelvir (NIR), in passaging and clinical samples. In SARS-CoV-2 replicons, E166V drastically decreased Washington (WA1) but not Omicron (BA.1) fitness (20- versus 2-fold), suggesting a lower barrier to resistance in the BA.1 strain and consistent with observed differences in respective nsp5 dimerization affinities. Crystal structures reveal a steric clash between the rigid, bulky NIR <i>tert</i>-butyl group and the β-branched Val<sup>166</sup>, disrupting the covalent binding of NIR to the catalytic Cys<sup>145</sup> and leading to high resistance in BA.1 and WA1 replicons. NIR-resistant replicons remained susceptible to GC376, which can still covalently bind Cys<sup>145</sup> by avoiding a steric clash with Val<sup>166</sup> through "wiggling and jiggling." Hence, strategic flexibility is a strategy that will help design second-generation antivirals against NIR-resistant viruses.
Medical subject headings
- SARS-CoV-2
- Drug Resistance, Viral
- Antiviral Agents
- Viral Nonstructural Proteins