Antiparasitic effect of a fraction enriched in tight-binding protease inhibitors isolated from the Caribbean coral Plexaura homomalla.

EMIR SALAS-SARDUY; AYMARA CABRERA-MUÑOZ; ANA CAUERHFF; YAMILE GONZALEZ-GONZALEZ; SEBASTIAN A. TREJO; AGUSTINA CHIDICHIMO; MARÍA DE LOS ANGELES CHAVEZ-PLANES; JUAN JOSE CAZZULO

EXPERIMENTAL PARASITOLOGY

ACADEMIC PRESS INC ELSEVIER SCIENCE

Lugar: Amsterdam; Año: 2013 vol. 135 p. 611 - 622

0014-4894

Malaria and American Trypanosomiasis constitute major global health problems. The continued emergence and spreading of resistant strains and the limited efficacy and/or safety of currently available therapeutic agents requires a constant search for new sources of antiparasitic compounds. In the present study, a fraction enriched in tight-binding protease inhibitors was isolated from the Caribbean coral Plexaura homomalla (Esper, 1792), functionally characterized and tested for their antiparasitic activity against Trypanosoma cruzi and Plasmodium falciparum. The resultant fraction was chromatographically enriched in tight-binding inhibitor active against Papain-like cysteine peptidases (92 %) and Pepsin-like aspartyl peptidases (8 %). Globally, the inhibitors present in the enriched fraction showed no competition with substrates and apparent Ki values of 1.99 nM and 4.81 nM for Falciapain 2 and Cruzipain, the major cysteine peptidases from P. falciparum and T. cruzi, respectively. The inhibitor-enriched fraction showed promising antiparasitic activity. It reduced the growth of the chloroquine-resistant P. falciparum strain Dd2 (IC50 = 0.46 µM) and promote the apparent accumulation of trophozoites, both consistent with a blockade in the hemoglobin degradation pathway.  At sub-micromolar concentrations, the inhibitor-enriched fraction reduced the infection of VERO cells by T. cruzi (CL Brener) trypomastigotes and interfered with intracellular differentiation and/or replication of parasites, matching with Cruzipain inhibition. This study provides new scientific evidence that confirms P. homomalla as an exceptional source of tight-biding protease inhibitors for different proteases with biomedical relevance, and suggests that either the individual inhibitors or the enriched fraction itself could be valuable as antiparasitic compounds.