INVESTIGADORES
FRACCAROLI Laura Virginia
congresos y reuniones científicas
Título:
Cruzipain inhibition by montelukast, a leukotriene receptor antagonist
Autor/es:
C. BELLERA; ML. SBARAGLINI; D. BALCAZAR; L. FRACCAROLI; A. TALEVI; C. CARRILLO
Lugar:
Mar del Plata
Reunión:
Congreso; X Congreso Argentino de Protozoología y Enfermedades Parasitarias; 2014
Resumen:
Cruzipain (Cz) is the major cystein protease of the hemoflagelate parasite Trypanosoma cruzi, etiologic agent of Chagas disease. This enzyme has been validated as drug target for novel antichagasic agents, being essential for T. cruzi amastigotes and playing a role in host-parasite interactions. In the present work, we have applied previously reported computational models to develop a ligand-based virtual screening campaign on two chemical repositories: DrugBank and Merck Index databases. The objective of this work is the discovery of novel antichagasic therapies in order to overcome the limitations of currently approved therapies, i.e. safety issues and low efficacy in the chronic stage of the disease replace current unsatisfactory therapies. Four of the identified drugs, namely: the leukotriene blocker montelukast, the antinociceptive and anti-inflammatory agent atranorin, the synthetic pyrethroid fluvalinate and the calcium blocker methoxyverapamil, were acquired and tested on Cz activity and epimastigotes proliferative assays. Testing the four compounds at a concentration of 100µM on purified Cz activity it was shown that only montelukast and atranorin had and inhibitory effect; however, only the first one maintained an inhibitory effect in lower concentrations showing a median inhibitory concentration (IC50) of 42.5±6.4 µM. Cultures of T. cruzi epimastigotes in the presence of montelukast showed inhibitory effects on proliferation, affecting the maximal cell density (treated: 29.6±2.8 million parasites/ml vs control: 59.0±9.2 million parasites/ml). This compound showed a median lethal dose (LD50) of 71.0±9.8 µM. Finding an a priori unpredictable inhibitory compound applying in silico screening confirms the utility of our models to identify, through a repurposing strategy, new trypanocidal therapeutics.