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Dipeptidyl nitrile derivatives have cytostatic effects against Leishmania spp. promastigotes

Quilles, José C., Tezuka, Daiane Y., Lopes, Carla D., Ribeiro, Fernanda L., Laughton, Charles A., de Albuquerque, Sérgio, Montanari, Carlos A., Leitão, Andrei
Experimental parasitology 2019 v.200 pp. 84-91
Leishmania amazonensis, Leishmania infantum, cell cycle checkpoints, cysteine proteinases, cytotoxicity, macrophages, mechanism of action, nitriles, parasites, promastigotes, proteolysis, therapeutics
Cysteine proteases are involved in critical cell processes to the protozoa from Leishmania genus, and their inhibition is a therapeutic alternative to treat the disease. In this work, derivatives of dipeptidyl nitriles acting as reversible covalent inhibitors of cysteine proteases were studied as cytostatic agents. The proteolytic activity inside the living and lysed parasite cells was quantified using a selective substrate for cysteine proteases (Z-FR-MCA) from Leishmania amazonensis and L. infantum. The overall proteolytic activity of intact cells and even cell extracts was only marginally affected at high concentrations, with the observation of cytostatic activity and cell cycle arrest of promastigotes. However, the cytotoxic effects were only observed for infected J774 macrophages, which impaired further analysis of the amastigote infection. Therefore, the proteolytic inhibition in intact L. amazonensis and L. infantum promastigotes had no relationship to the cytostatic activity, which emphasizes that these dipeptidyl nitriles act through another mechanism of action.