Calpeptin is a potent cathepsin inhibitor and drug candidate for SARS-CoV-2 infections.
Patrick Y A ReinkeEdmarcia Elisa de SouzaSebastian GüntherSven FalkeJulia LieskeWiebke EwertJure LobodaAlexander HerrmannAida Rahmani MashhourKatarina KarničarAleksandra UsenikNataša LindičAndreja SekirnikViviane Fongaro BotossoGláucia Maria Machado SantelliJosana KapronezaiMarcelo Valdemir de AraújoTaiana Tainá Silva-PereiraAntônio Francisco de Souza FilhoMariana Silva TavaresLizdany Flórez-ÁlvarezDanielle Bruna Leal de OliveiraEdison Luiz DurigonPaula Roberta GiarettaMarcos Bryan HeinemannMaurice HauserBrandon SeychellHendrik BöhlerWioletta RutMarcin Dra GTobias BeckRussell J CoxHenry N ChapmanChristian BetzelWolfgang BrehmWinfried HinrichsGregor EbertSharissa L LathamAna Marcia de Sá GuimarãesDusan TurkCarsten WrengerAlke MeentsPublished in: Communications biology (2023)
Several drug screening campaigns identified Calpeptin as a drug candidate against SARS-CoV-2. Initially reported to target the viral main protease (M pro ), its moderate activity in M pro 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 reduces the viral load in the trachea. Despite a higher risk of side effects, an intrinsic advantage in targeting host proteins is their mutational stability in contrast to highly mutable viral targets. Here we show that the inhibition of cathepsins, a protein family of the host organism, by calpeptin is a promising approach for the treatment of SARS-CoV-2 and potentially other viral infections.