This article presents an overview of the currently available drugs
nifurtimox (NFX) and
benznidazole (BZN) used against Trypanosoma cruzi, the aetiological agent of
Chagas disease; herein we discuss their limitations along with potential alternatives with a focus on
ergosterol biosynthesis inhibitors (EBI). These compounds are currently the most advanced candidates for new
anti-T. cruzi agents given that they block de novo production of 24-alkyl-sterols, which are essential for parasite survival and cannot be replaced by a host's own
cholesterol. Among these compounds, new
triazole derivatives that inhibit the parasite's C14alpha
sterol demethylase are the most promising, as they have been shown to have curative activity in murine models of acute and chronic
Chagas disease and are active against NFX and BZN-resistant T. cruzi strains; among this class of compounds,
posaconazole (Schering-Plough Research Institute) and
ravuconazole (Eisai Company) are poised for clinical trials in
Chagas disease patients in the short term. Other T. cruzi-specific EBI, with in vitro and in vivo potency, include
squalene synthase,
lanosterol synthase and
squalene epoxidase-inhibitors as well as compounds with dual mechanisms of action (
ergosterol biosynthesis inhibition and
free radical generation), but they are less advanced in their development process. The main putative advantages of EBI over currently available
therapies include their higher potency and selectivity in both acute and
chronic infections, activity against NFX and BZN-resistant T. cruzi strains, and much better tolerability and safety profiles. Limitations may include complexity and cost of manufacture of the new compounds. As for any new drug, such compounds will require extensive clinical testing before being introduced for clinical use, and the complexity of such studies, particularly in chronic patients, will be compounded by the current limitations in the verification of true parasitological cures for T. cruzi
infections.