Combating Chagas Disease Through Inhibition of Tiam1, a Rho GTPase Guanine Nucleotide Exchange Factor

Abstract

Chagas disease is a major cardiovascular affliction primarily endemic to Latin American countries, affecting some ten to twelve million people worldwide. The currently available drugs, Benznidazole and Nifurtimox, are ineffecteive in the disease's chronic stages and induce severe side effects. In an attempt to improve this situation we use an in silico drug repurposing strategy to correlate drug-protein interactions with positive clinical outcomes. The strategy involves a protein functional site similarity search, along with computational docking studies and, given the findings, a phosphatidylinositol (PIP) strip test to determine the activity of Posaconazole, a recently developed antifungal triazole, in conjunction with Tiam1, a Rho GTPase Guanine Nucleotide Exchange Factor. The results from both computational and in vitro studies indicate possible inhibition of phosphoinositides via Posaconazole, preventing Rho GTPase-induced proliferation of T. cruzi, the etiological agent of Chagas Disease. SynopsisWhile Benznidazole and Nifurtimox are effective in the acute phase of Chagas' disease, their inefficacy in the disease's chronic phase and severe side effects motivate the search for more novel treatment pathways. Antifungal triazoles have shown promise in murine models of Chagas. Using a computational platform, the authors find that these drugs may be used to combat Chagas Disease through a previously unknown mechanism. If correct, this model could be used to motivate the production of new vaccines for Chagas. Furthermore, the model demonstrates the efficacy of computational testing in the preliminary search for effective drug candidates.