New research on nirmatrelvir resistance in SARS-CoV-2 using powerful replicon cell culture systems SARSCoV2 nirmatrelvir COVID childrensatl EmoryUniversity biorxivpreprint
Study: Nirmatrelvir Resistance in SARS-CoV-2 Omicron_BA.1 and WA1 Replicons and Escape Strategies. Image Credit: Juan Gaertner / Shutterstock
About the study In the present study, the researchers used site-directed mutagenesis to design mutations at the residues flanking the nirmatrelvir binding site based on crystal structures of the nsp5 of the WA.1 SARS-CoV-2 strain. A luciferase complementation reporter assay and human embryonic kidney 293 cells were used to assess the impact of the nsp5 mutations on the protease activity. The assay indicates the absence of protease cleavage through increased NanoLuc activity.
Results The results indicated that the E166V mutation granted close to 55-fold resistance against nirmatrelvir to both WA.1 and BA.1 strains. However, in the WA.1 strain, the mutation also resulted in a 20-fold reduction in fitness, while in the BA.1 strain, the reduction in fitness was only two-fold. Furthermore, the L50F mutation in the WA.1 strain restored its fitness.
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