Identification of Dual Inhibitors Targeting Main Protease (Mpro) and Cathepsin L as Potential Anti-SARS-CoV-2 Agents

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 mu M against SARS-CoV-2 M-pro; meanwhile, K-i values ranging from 0.004 to 0.701 mu M 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 CC50 values >100 mu M. 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.