VFV as a new effective CYP51 structure-derived drug candidate for chagas disease and visceral leishmaniasis

Galina I. Lepesheva, Tatiana Y. Hargrove, Girish Rachakonda, Zdzislaw Wawrzak, Sébastien Pomel, Sandrine Cojean, Pius N. Nde, W. David Nes, Charles W. Locuson, M. Wade Calcutt, Michael R. Waterman, J. Scott Daniels, Philippe M. Loiseau, Fernando Villalta

Research output: Contribution to journalArticlepeer-review

52 Scopus citations


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. Recently, 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 experiments, 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 distribution characterize VFV as a promising new drug candidate.

Original languageEnglish
Pages (from-to)1439-1448
Number of pages10
JournalJournal of Infectious Diseases
Issue number9
StatePublished - Nov 1 2015


  • Chagas disease
  • Leishmania
  • Trypanosoma cruzi
  • VFV
  • VNI
  • inhibition
  • sterol 14?-demethylase (CYP51)
  • sterol biosynthesis
  • structure-based drug design
  • visceral leishmaniasis


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