Identification of antichagasic activity of clofazimine, benidipine and saquinavir through computer-aided drug repurposing

CAROLINA BELLERA; BALCAZAR DARIO; VANRELL CRISTINA; LABRIOLA CARLOS; GÁLVEZ JORGE; BRUNO BLANCH LUIS; ROMANO PATRICIA; CARRILLO CAROLINA; TALEVI ALAN

Mar del Plata

Congreso; X Congreso Argentino de Protozoología y Enfermedades Parasitarias; 2014

Cruzipain (Cz) is the main cystein protease of Trypanosoma cruzi and has previously beenvalidated as new drug target, proving to be essential for replication of the intracellular formof T. cruzi and playing a role in host-parasite interactions. We present an integrativeapproach for the search of novel antichagasic agents, including virtual screening (VS) ofCz inhibitors oriented to knowledge-based drug repositioning, and subsequentbiochemical, cellular and pre-clinical testing. A computational classificatory model capableof discriminating between Cz inhibitors and non-inhibitors was obtained usingDESMOL11software (Molecular Topology & Drug Design Unit. University of Valencia,Spain) and Statistica 10 (statsoft 2010). Such model was validated and applied in the VSof Merck Index 12th. 154 compounds were selected as promising candidates, 34 of themcorrespond to approved drugs, which are the most favorable, direct candidates forrepositioning purposes, four of which were tested in enzymatic assays and epimastigotecultures. Three of them (clofazimine, benidipine and saquinavir) showed clear inhibitoryeffects on Cz and antiproliferative effects on T. cruzi.) Based on pharmacological criteria,clofazimine and benidipine were moved to preclinical stage, where they were effective in amice model of acute infection. Clofazimine also reduced the allocation of T. cruzi nests incardiac tissue, suggesting it could be useful to prevent the development of cardiacdamage in Chagas disease. The present work successfully integrates computer-aideddrug discovery with molecular and cellular biology and preclinical testing, confirming theutility of VS to develop knowledge-based drug repurposing.