Calpeptin is a potent cathepsin inhibitor and drug candidate for SARS-CoV-2 infections (preprint)

ABSTRACT

Several drug screening campaigns identified Calpeptin as a drug candidate against SARS-CoV-2. Initially reported to target the viral main protease (Mpro), its moderate activity in Mpro inhibition assays hints at a second target. Indeed, we show that Calpeptin is an extremely potent cysteine cathepsin inhibitor, a finding additionally supported by X-ray crystallography. Cell infection assays proved Calpeptin’s efficacy against SARS-CoV-2. Treatment of SARS-CoV-2-infected Golden Syrian hamsters with sulfonated Calpeptin at a dose of 1 mg/kg body weight significantly reduces the viral load in the trachea. Our results show that the inhibition of cathepsins, a protein family of the host organism, is a promising approach for the treatment of SARS-CoV-2 and potentially other viral infections. An intrinsic advantage in targeting host proteins is their mutational stability in contrast to highly mutable viral targets.