Journal of Medicinal Chemistry
Journal of Medicinal Chemistry
5 years ago

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

Development of Novel Peptide-Based Michael Acceptors Targeting Rhodesain and Falcipain-2 for the Treatment of Neglected Tropical Diseases (NTDs)
Ute A. Hellmich, Philip J. Rosenthal, Ira Schmid, Peter R. Wich, Annika Wagner, Silvana Grasso, Kathrin Ulrich, Santo Previti, Sandro Cosconati, Maria Zappalà, Jiri Gut, Tanja Schirmeister, Giorgio Amendola, R. Luise Krauth-Siegel, Khawla Chouchene, Roberta Ettari
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 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 Trypanosoma brucei brucei (EC50 = 2.97 μM), thus being considered as a novel lead compound for the discovery of novel effective antitrypanosomal agents.

Publisher URL: http://dx.doi.org/10.1021/acs.jmedchem.7b00405

DOI: 10.1021/acs.jmedchem.7b00405

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