Chagas disease (American trypanosomiasis) is a deadly insect vector-borne infection caused by a variety of naturally occurring strains of the unicellular eukaryotic parasite Trypanosoma cruzi. The disease is endemic in South and Central America and is becoming a serious global health problem due to human migration. In the USA, the situation is particularly alarming because of the broadening of the vector distribution area. Kissing bug bites has been reported in 44 states, and an estimate suggests that there are &gt;2 million infected here. The only two drugs available in South America (benznidazole and nifurtimox) are highly toxic, have not been approved by FDA and are not prescribed in the USA. New, safer and more efficient therapies are urgently needed. Similar to fungi, the life of T. cruzi depends on the production of endogenous sterols. Ergosterol derivatives serve as essential membrane components and regulate the parasite multiplication and morphological transformation. The attempts to repurpose antifungal agents for Chagas disease have been undertaken. However, the drug candidate ravuconazole exhibited bioavailability problems, and the 20% success rate of the drug posaconazole has been declared as a failure. Both these compounds inhibit fungal sterol 14α-demethylase (CYP51), the cytochrome P450 enzyme that has about 25% sequence identity to the T. cruzi ortholog. We have solved the X-ray structure of T. cruzi CYP51 in complex with 16 inhibitors, including posaconazole, built the structure-based 3D-inhibitory pharmacophore, identified a novel, highly potent inhibitor (VNI) that cures the acute and chronic Chagas disease in mice infected with Tulahuen strain of T. cruzi, and used the structural information for further VNI scaffold development aimed at broadening its antiprotozoan spectrum of activity (VFV). VFV completely suppresses parasitemia in mice infected with Tulahuen, Y, and Colombiana T. cruzi and is more potent than VNI against mice infection with Leishmania donovani. Non-toxic, non-mutagenic, having favorable pharmacokinetics, high oral bioavailability (maximal plasma concentration 25 µM vs. ~6 µM for posaconazole and ~1 µM for ravuconazole) and broad tissue distribution, VFV is a promising drug candidate suitable for entering clinical trials for Chagas disease.

CYP51 inhibitors for Chagas disease

254th National Meeting (2017)

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