Calpeptin is a potent cathepsin inhibitor and drug candidate for SARS-CoV-2 infections
P. Reinke, Edmárcia Elisa de Souza, Sebastian Günther, Sven Falke, J. Lieske, Wiebke Ewert, Jure Loboda, Alexander Herrmann, Aida Rahmani Mashhour, Katarina Karničar, Aleksandra Usenik, Nataša Lindič, Andreja Sekirnik, Viviane Fongaro Botosso, Gláucia Maria Machado‐Santelli, Josana Kapronezai, Marcelo Valdemir de Araújo, Taiana Tainá Silva‐Pereira, Antônio Francisco de Souza Filho, Mariana Silva Tavares, Lizdany Flórez‐Álvarez, Danielle Bruna Leal Oliveira, Edison Luíz Durigon, Paula R. Giaretta, Marcos Bryan Heinemann, Maurice Hauser, B. Seychell, Hendrik Böhler, Wioletta Rut, Marcin Drąg, Tobias Beck, Russell J. Cox, Henry N. Chapman, Christian Betzel, W. Brehm, Winfried Hinrichs, Gregor Ebert, Sharissa L. Latham, Ana M. S. Guimarães, Vito Türk, Carsten Wrenger, Alke Meents
Abstract
Abstract 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.