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

Author(s):Show less -

Burtoloso, Antonio C. B. ; de Albuquerque, Sergio ; Furber, Mark ; Gomes, Juliana C. ; Goncalez, Cristiana ; Kenny, Peter W. ; Leitao, Andrei ; Montanari, Carlos A. ; Quilles Junior, Jose Carlos ; Ribeiro, Jean F. R. ; Rocha, Josmar R.

• Document type: Journal article
• Source: PLoS Neglected Tropical Diseases; v. 11, n. 2 FEB 2017.
• Web of Science Citations: 5

Abstract

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 mu M to 1 mu M 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 mu M and 0.25 mu M) 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. (AU)

• FAPESP's process: 13/18009-4 - Molecular design, synthesis and trypanocidal activity of cruzain reversible covalent inhibitors
• Grantee: Carlos Alberto Montanari
• Support Opportunities: Research Projects - Thematic Grants