VFV as a New Effective CYP51 Structure-Derived Drug Candidate for Chagas Disease and Visceral

Sterol 14α-demethylases (CYP51) are the enzymes essential for sterol biosynthesis. They serve as clinical targets for antifungal azoles and are considered as targets for treatment of human Trypanosomatidae infections. Re-cently, we have shown that VNI, a potent and selective inhibitor of trypanosomal CYP51 that we identified and structurally characterized in complex with the enzyme, can cure the acute and chronic forms of Chagas disease. The purpose of this work was to apply the CYP51 structure/function for further development of the VNI scaffold. As anticipated, VFV (R)-N-(1-(3,4′-difluorobiphenyl-4-yl)-2-(1H-imidazol-1-yl)ethyl)-4-(5-phenyl-1,3,4-oxadiazol-2-yl)benzamide, the derivative designed to fill the deepest portion of the CYP51 substrate-binding cavity, reveals a broader antiprotozoan spectrum of action. It has stronger antiparasitic activity in cellular ex-periments, cures the experimental Chagas disease with 100 % efficacy, and suppresses visceral leishmaniasis by 89 % (vs 60 % for VNI). Oral bioavailability, low off-target activity, favorable pharmacokinetics and tissue dis-tribution characterize VFV as a promising new drug candidate. Keywords. Chagas disease; Trypanosoma cruzi; visceral leishmaniasis; Leishmania; sterol biosynthesis; sterol 14α-demethylase (CYP51); inhibition; VNI; VFV; structure-based drug design. Human infections with Trypanosomatidae represent a severe global health problem [1, 2]. Currently, thes