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