Resistance mechanisms of SARS-CoV-2 3CLpro to the non-covalent inhibitor WU-04
Lijing Zhang,
Xuping Xie,
Hannan Luo
et al.
Abstract:Drug resistance poses a significant challenge in the development of effective therapies against SARS-CoV-2. Here, we identified two double mutations, M49K/M165V and M49K/S301P, in the 3C-like protease (3CLpro) that confer resistance to a novel non-covalent inhibitor, WU-04. Crystallographic analysis indicates that the M49K mutation destabilizes the WU-04 binding pocket, impacting the binding of WU-04 more significantly than the binding of 3CLpro substrates. The M165V mutation directly interferes with WU-04 bin… Show more
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