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J Infect Dis. 2015 Nov 1;212(9):1439-48. doi: 10.1093/infdis/jiv228. Epub 2015 Apr 15.

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

Author information

1
Department of Biochemistry School of Medicine Center for Structural Biology, Vanderbilt University.
2
Department of Biochemistry School of Medicine.
3
Department of Microbiology and Immunology, Meharry Medical College, Nashville, Tennessee.
4
Synchrotron Research Center, Life Science Collaborative Access Team, Northwestern University, Argonne, Illinois.
5
Antiparasitic Chemotherapy, UMR 8076 CNRS BioCIS, University Paris-Sud, Chatenay-Malabry, France.
6
Department of Chemistry and Biochemistry, Center for Chemical Biology, Texas Tech University, Lubbock.
7
Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee.

Abstract

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.

KEYWORDS:

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

PMID:
25883390
PMCID:
PMC4601915
DOI:
10.1093/infdis/jiv228
[Indexed for MEDLINE]
Free PMC Article

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