The heme A synthase Cox15, as a target of redox-active 3-benzylmenadiones with antiparasitic activity

TL;DR

This paper identifies Cox15 as a new drug target for treating Chagas disease by studying how cruzidione, a potent compound, affects the parasite and yeast models.

Contribution

The study reveals Cox15 as a novel antiparasitic drug target through the mode of action of cruzidione.

Findings

Cruzidione's primary target is the heme A synthase Cox15, as shown by yeast sensitivity and enzyme loss.

Cruzidione reduces heme content in T. cruzi, likely by inhibiting heme A synthase.

NADH-dehydrogenase is involved in cruzidione bioactivation, similar to its role with plasmodione.

Abstract

Chagas disease, caused by Trypanosoma cruzi, is a neglected parasitic infection. The very limited arsenal of anti-T. cruzi treatments calls for the development of new drugs. Recently, a library of 3-benzylmenadione derivatives was synthesized, with cruzidione being the most efficient and specific compound against the parasite. To decipher its mode of action, we used the yeast Saccharomyces cerevisiae as a model. Evidence pinpointed at the heme A synthase Cox15 as a primary target of cruzidione: (i) a mutation in Cox15 (i.e., S429F) renders the yeast cells highly sensitive to the drug, (ii) treatment with cruzidione led to the loss of cytochrome c oxidase, an enzyme that relies on heme A as an essential cofactor, and (iii) replacement of the yeast Cox15 by T. cruzi enzyme resulted in a high sensitivity to cruzidione. We then investigated the effect of cruzidione in T. cruzi and observed a significant reduction in the heme contents, most likely involving the inhibition of the heme A synthase. This, in turn, led to a decrease in O2 consumption by the parasite. Finally, using the yeast model, we showed that, similar to what we previously found for the antimalarial benzylmenadione plasmodione, NADH-dehydrogenase plays a key role in cruzidione bioactivation. We proposed that the reduced benzoylmenadione metabolites, produced by the reaction with NADH-dehydrogenase, act as Cox15 inhibitors. This study, through the identification of the mode of action of cruzidione, highlighted Cox15 as a novel target for antiparasitic drugs.

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