Identification of Dual Inhibitors Targeting Main Protease (M<sup>pro</sup>) and Cathepsin L as Potential Anti-SARS-CoV-2 Agents
Santo Previti, Roberta Ettari, Elsa Calcaterra, Michele Roggia, Benito Natale, Annabelle C. Weldert, Christin Müller, Florian Salisch, Anna Irto, Rosalia Maria Cigala, John Ziebuhr, Tanja Schirmeister, Sandro Cosconati, Maria Zappalà
Abstract
In this structure–activity relationship (SAR) study, we report the development of dual inhibitors with antiviral properties targeting the SARS-CoV-2 main protease (M pro ) and human cathepsin L (hCatL). The novel molecules differ in the aliphatic amino acids at the P2 site and the fluorine position on the phenyl ring at the P3 site. The identified dual inhibitors showed K i values within 1.61 and 10.72 μM against SARS-CoV-2 M pro; meanwhile, K i values ranging from 0.004 to 0.701 μM toward hCatL were observed. A great interdependency between the nature of the side chain at the P2 site and the position of the fluorine atom was found. Three dual-targeting inhibitors exhibited antiviral activity in the low micromolar range with CC 50 values >100 μM. Docking simulations were executed to gain a deeper understanding of the SAR profile. The findings herein collected should be taken into consideration for the future development of dual SARS-CoV-2 M pro /hCatL inhibitors.