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 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.
Highlights
Chagas disease, known as American trypanosomiasis, is a significant public health problem in Latin America [1,2,3]
We have identified three compounds with anti-trypanosomal effects on the infective T. cruzi CL Brener form prevalent in various regions of PLOS Neglected Tropical Diseases | DOI:10.1371/journal.pntd
Chagas disease is caused by the protozoan parasite T. cruzi, which is transmitted by bloodsucking reduviid bugs of the subfamily Triatominae [1,2,3]
Summary
Known as American trypanosomiasis, is a significant public health problem in Latin America [1,2,3]. Considered to be a neglected tropical disease (NTD), Chagas disease is becoming more prevalent outside Latin America due to increased migration [4]. The antifungal drug posaconazole showed limited curative potential in a randomized clinical trial against chronic T. cruzi infection [7] and this has stimulated debate [8,9] about the extent to which the result might have been predicted using in vivo imaging. The paucity of therapeutic options for chronic Chagas disease has fueled interest in the discovery of new macromolecular targets and led to collaborative efforts worldwide, including initiatives such as Drugs for Neglected Diseases (DNDi) [10]
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