Nirmatrelvir-Resistant Mutations in SARS-CoV-2 Mpro Enhance Host Immune Evasion via Cleavage of NF-κB Essential Modulator

Nirmatrelvir is a SARS-CoV-2 Mpro inhibitor in Paxlovid. Patients treated with it often produce mutant viruses in which the Mpro resists Nirmatrelvir inhibition. A common interpretation is that the mutations allow the virus to escape inhibition, but here we report that these mutations enable the protease to more effectively cleave the host protein NF-kappa-B essential modulator (NEMO), which weakens the immune response, improves viral replication, and may contribute to long COVID.