Fig. 4: 3CLpro mutations that confer resistance to WU-04, ensitrelvir and nirmatrelvir decreased the catalytic activity and thermostability of 3CLpro.
From: Resistance mechanisms of SARS-CoV-2 3CLpro to the non-covalent inhibitor WU-04
a–c Occupancy of the substrate-binding pocket of SARS-CoV-2 3CLpro by the non-covalent inhibitors WU-04 (a) and ensitrelvir (b), and the covalent inhibitor nirmatrelvir (c). d–f Interactions between SARS-CoV-2 3CLpro and WU-04 (d), between SARS-CoV-2 3CLpro and ensitrelvir (e), and between SARS-CoV-2 3CLpro and nirmatrelvir (f). Hydrogen bonds are indicated by green dash lines. The residue mutations that may confer resistance to the three inhibitors are colored orange. g Relative catalytic activities of the drug-resistant 3CLpro mutants. The catalytic activity (kcat/Km) of each mutant was evaluated using a FRET-based assay with three independent measurements, and then normalized to that of the WT 3CLpro. h Changes in the melting temperature (Tm) of SARS-CoV-2 3CLpro induced by drug resistance mutations. The Tm of each mutant was evaluated using a thermal shift assay. The data represent the means ± SD of technical triplicate.
