Open AccessAnti-trypanosomal activity of non-peptidic nitrile-based cysteine protease inhibitors
Author(s) -
Antonio C. B. Burtoloso,
Sérgio de Albuquerque,
Mark Furber,
Juliana C. Gomes,
Cristiana Gonçalez,
Peter W. Kenny,
Andrei Leitão,
Carlos Alberto Montanari,
José Carlos Quilles,
Jean Francisco Rosa Ribeiro,
Jansle Vieira Rocha
Publication year - 2017
Publication title -
plos neglected tropical diseases
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.99
H-Index - 135
eISSN - 1935-2735
pISSN - 1935-2727
DOI - 10.1371/journal.pntd.0005343
Subject(s) - cysteine protease , proteases , cysteine , trypanosoma cruzi , protease , chemistry , cathepsin c , biochemistry , chagas disease , cathepsin b , cathepsin , enzyme , recombinant dna , pharmacology , biology , virology , parasite hosting , world wide web , computer science , gene
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 EC 50 values (0.12 μM and 0.25 μM) that were an order of magnitude lower than the corresponding K i 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.