Anti-trypanosomal activity of non-peptidic nitrile-based cysteine protease inhibitors.

The cysteine protease cruzipain is considered to be a validated target for therapeutic intervention in the treatment of Chagas disease. Anti-trypanosomal activity against the CL Brener strain of T. cruzi was observed in the 0.1 μM to 1 μM range for three nitrile-based cysteine protease inhibitors ba...

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Bibliographic Details
Published in:PLOS Neglected Tropical Diseases
Main Authors: Antonio C B Burtoloso, Sérgio de Albuquerque, Mark Furber, Juliana C Gomes, Cristiana Gonçalez, Peter W Kenny, Andrei Leitão, Carlos A Montanari, José Carlos Quilles, Jean F R Ribeiro, Josmar R Rocha
Format: Article in Journal/Newspaper
Language:English
Published: Public Library of Science (PLoS) 2017
Subjects:
Arctic medicine. Tropical medicine
RC955-962
Public aspects of medicine
RA1-1270
Arctic
Online Access:https://doi.org/10.1371/journal.pntd.0005343
https://doaj.org/article/c040bb0a668b427ebd712530ad099df5
Description
Summary:The cysteine protease cruzipain is considered to be a validated target for therapeutic intervention in the treatment of Chagas disease. Anti-trypanosomal activity against the CL Brener strain of T. cruzi was observed in the 0.1 μM to 1 μM range for three nitrile-based cysteine protease inhibitors based on two scaffolds known to be associated with cathepsin K inhibition. The two compounds showing the greatest potency against the trypanosome were characterized by EC50 values (0.12 μM and 0.25 μM) that were an order of magnitude lower than the corresponding Ki values measured against cruzain, a recombinant form of cruzipain, in an enzyme inhibition assay. This implies that the anti-trypanosomal activity of these two compounds may not be explained only by the inhibition of the cruzain enzyme, thereby triggering a putative polypharmacological profile towards cysteine proteases.

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