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

Authors :
Lepesheva GI
Hargrove TY
Rachakonda G
Wawrzak Z
Pomel S
Cojean S
Nde PN
Nes WD
Locuson CW
Calcutt MW
Waterman MR
Daniels JS
Loiseau PM
Villalta F
Source :
The Journal of infectious diseases [J Infect Dis] 2015 Nov 01; Vol. 212 (9), pp. 1439-48. Date of Electronic Publication: 2015 Apr 15.
Publication Year :
2015

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.<br /> (© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Details

Language :
English
ISSN :
1537-6613
Volume :
212
Issue :
9
Database :
MEDLINE
Journal :
The Journal of infectious diseases
Publication Type :
Academic Journal
Accession number :
25883390
Full Text :
https://doi.org/10.1093/infdis/jiv228