Heat Shock Protein Inhibitor Tanespimycin (17AAG) Suppresses SARS‐CoV‐2 Main Protease Activity and Is More Potent Than Clinically Approved Antiviral Nirmatrelvir

The COVID‐19 pandemic caused by SARS‐CoV‐2 created a global health crisis, and the virus still circulates, mutates, and causes illness and death. Vaccination remains the primary defense, but effectiveness can be reduced in immunocompromised individuals and against new variants, and clinically approved antivirals are limited by side effects, drug interactions, and resistance. Herein, we propose a novel application of tanespimycin (17AAG), the chaperone heat shock protein (HSP)90 inhibitor, as an antiviral against the SARS‐CoV‐2 main protease (M ^pro ). M ^pro , due to its indispensable role in viral replication and absence of expression in the host, represents a key target for drug development. Through biochemical and cell‐based assays, structural analysis, and resistance‐mutant testing, we present data showing that 17AAG covalently binds to the active‐site cysteine of M ^pro , disrupts its secondary structure, and protects cells from M ^pro ‐induced toxicity more effectively than nirmatrelvir. We further showed that 17AAG retains its covalent binding and structure‐disrupting activity against the nirmatrelvir‐resistance M165I variant. Additionally, since HSP90 is important for viral protein stability, virion assembly, and modulation of host immune response, 17AAG is a promising, versatile drug candidate that could accelerate antiviral development for COVID‐19.