Identification of Dual Inhibitors Targeting Main Protease (M^pro) 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 (Mpro) 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 Ki values within 1.61 and 10.72 μM against SARS-CoV-2 Mpro; meanwhile, Ki 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 CC50 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 Mpro/hCatL inhibitors

Development of Novel Peptide-Based Michael Acceptors Targeting Rhodesain and Falcipain‑2 for the Treatment of Neglected Tropical Diseases (NTDs)

This paper describes the development of a class of peptide-based inhibitors as novel antitrypanosomal and antimalarial agents. The inhibitors are based on a characteristic peptide sequence for the inhibition of the cysteine proteases rhodesain of Trypanosoma brucei rhodesiense and falcipain-2 of Plasmodium falciparum. We exploited the reactivity of novel unsaturated electrophilic functions such as vinyl-sulfones, -ketones, -esters, and -nitriles. The Michael acceptors inhibited both rhodesain and falcipain-2, at nanomolar and micromolar levels, respectively. In particular, the vinyl ketone <b>3b</b> has emerged as a potent rhodesain inhibitor (<i>k</i>_2nd = 67 × 10⁶ M^–1 min^–1), endowed with a picomolar binding affinity (<i>K</i>_i = 38 pM), coupled with a single-digit micromolar activity against Trypanosoma brucei brucei (EC₅₀ = 2.97 μM), thus being considered as a novel lead compound for the discovery of novel effective antitrypanosomal agents