Antiparasitic Activity of Sterol 14α-Demethylase (CYP51) Inhibitor VNI against Drug-Resistant Strains of Trypanosoma cruzi: In vitro and In vivo Studies.

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Antiparasitic Activity of Sterol 14α-Demethylase (CYP51) Inhibitor VNI against Drug-Resistant Strains of Trypanosoma cruzi: In vitro and In vivo Studies.

Antimicrob Agents Chemother. 2013 Jun 17;

Authors: Soeiro MD, de Souza EM, da Silva CF, da Gama Jaen Batista D, Batista MM, Pavão BP, Araújo JS, Aiub CA, da Silva PB, Lionel J, Britto C, Kim K, Sulikowski G, Hargrove TY, Waterman MR, Lepesheva GI

Abstract
Chagas disease affects more than 10 million people worldwide and yet, historically known as the disease of the poor, remains highly neglected. Two currently available drugs exhibit severe toxicity and low effectiveness, especially in the chronic phase, while new drug discovery has been halted for years by the lack of interest from the pharmaceutical companies. Although attempts to repurpose antifungal drugs posaconazole and ravuconazole (inhibitors of fungal sterol 14α-demethylase (CYP51)) are finally in progress, development of cheaper and more efficient, preferably Trypanosoma cruzi specific chemotherapies would be highly advantageous. We have recently reported that the experimental T.cruzi CYP51 inhibitor, VNI, cures with 100% survival and 100% parasitological clearance both the acute and chronic murine infections with the Tulahuen strain of T.cruzi. In this work, we further explored VNI potential by assaying nitroderivatives-resistant T.cruzi strains, Y and Colombiana, in the highly stringent protocols of the acute infection. The data show high antiparasitic efficacy of VNI and its derivative (VNI/VNF) against both relevant for mammalian host infection forms of T.cruzi (bloodstream and amastigotes) with the in vivo potency at 25mg/kg/b.i.d similar to that of benznidazole at 100mg/kg/day. Transmission electron microscopy and reverse mutation tests were performed to explore cellular ultrastructural and mutagenic aspects of VNI, respectively. No mutagenic potential could be noticed by Ames test up to 3.5 μM and the main ultrastructural damage induced by VNI in T.cruzi was related to Golgi and endoplasmic reticulum organization with membrane blebs presenting autophagic phenotype. Thus, these preliminary studies confirm VNI as a very promising trypanocidal drug candidate for Chagas disease therapy.

PMID: 23774435 [PubMed - as supplied by publisher]

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