Mapping the S1 and S1' subsites of cysteine proteases with new dipeptidyl nitrile inhibitors as trypanocidal agents.

• Published in: PLOS Neglected Tropical Diseases
• Main Authors: Lorenzo Cianni, Carina Lemke, Erik Gilberg, Christian Feldmann, Fabiana Rosini, Fernanda Dos Reis Rocho, Jean F R Ribeiro, Daiane Y Tezuka, Carla D Lopes, Sérgio de Albuquerque, Jürgen Bajorath, Stefan Laufer, Andrei Leitão, Michael Gütschow, Carlos A Montanari
• Format: Article in Journal/Newspaper
• Language: English
• Published: Public Library of Science (PLoS) 2020
• Subjects: Arctic medicine. Tropical medicine; RC955-962; Public aspects of medicine; RA1-1270; Arctic
• Online Access: https://doi.org/10.1371/journal.pntd.0007755; https://doaj.org/article/3510716dcbcc410e83482bb1244acca6

The cysteine protease cruzipain is considered to be a validated target for therapeutic intervention in the treatment of Chagas disease. A series of 26 new compounds were designed, synthesized, and tested against the recombinant cruzain (Cz) to map its S1/S1´ subsites. The same series was evaluated on a panel of four human cysteine proteases (CatB, CatK, CatL, CatS) and Leishmania mexicana CPB, which is a potential target for the treatment of cutaneous leishmaniasis. The synthesized compounds are dipeptidyl nitriles designed based on the most promising combinations of different moieties in P1 (ten), P2 (six), and P3 (four different building blocks). Eight compounds exhibited a Ki smaller than 20.0 nM for Cz, whereas three compounds met these criteria for LmCPB. Three inhibitors had an EC50 value of ca. 4.0 μM, thus being equipotent to benznidazole according to the antitrypanosomal effects. Our mapping approach and the respective structure-activity relationships provide insights into the specific ligand-target interactions for therapeutically relevant cysteine proteases.