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

Santo Preveti, Roberta Ettari, Sandro Cosconati, Giorgio Amendola, Khawla Chouchene, Annika Wagner, Ute A. Hellmich, Kathrin Ulrich, R. Luise Krauth-Siegel, Peter R. Wich, Ira Schmid, Tanja Schirmeister, Jiri Gut, Philip J. Rosenthal, Silvana Grasso, and Maria Zappalà

J. Med. Chem. 2017

DOI: 10.1021/acs.jmedchem.7b00405

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 T. b. rhodesiense and falcipain-2 of P. 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 level, respectively. In particular, the vinyl ketone 3b has emerged as a potent rhodesain inhibitor (k2nd= 67•106 M-1 min-1), endowed with a picomolar binding affinity (Ki = 38 pM), coupled with a single-digit micromolar activity against T. b. brucei (EC50 = 2.97 µM), thus being considered as a novel lead compound for the discovery of novel effective antitrypanosomal agents.