title: VFV as a New Effective CYP51 Structure-Derived Drug Candidate for Chagas Disease and Visceral Leishmaniasis.
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.
authors.affiliation: Department of Biochemistry School of Medicine Center for Structural Biology, Vanderbilt University.
authors.forename: Galina I
authors.initials: GI
authors.lastname: Lepesheva
authors.affiliation: Department of Biochemistry School of Medicine.
authors.forename: Tatiana Y
authors.initials: TY
authors.lastname: Hargrove
authors.affiliation: Department of Microbiology and Immunology, Meharry Medical College, Nashville, Tennessee.
authors.forename: Girish
authors.initials: G
authors.lastname: Rachakonda
authors.affiliation: Synchrotron Research Center, Life Science Collaborative Access Team, Northwestern University, Argonne, Illinois.
authors.forename: Zdzislaw
authors.initials: Z
authors.lastname: Wawrzak
authors.affiliation: Antiparasitic Chemotherapy, UMR 8076 CNRS BioCIS, University Paris-Sud, Chatenay-Malabry, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Pomel
authors.affiliation: Antiparasitic Chemotherapy, UMR 8076 CNRS BioCIS, University Paris-Sud, Chatenay-Malabry, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Cojean
authors.affiliation: Department of Microbiology and Immunology, Meharry Medical College, Nashville, Tennessee.
authors.forename: Pius N
authors.initials: PN
authors.lastname: Nde
authors.affiliation: Department of Chemistry and Biochemistry, Center for Chemical Biology, Texas Tech University, Lubbock.
authors.forename: W David
authors.initials: WD
authors.lastname: Nes
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Charles W
authors.initials: CW
authors.lastname: Locuson
authors.affiliation: Department of Biochemistry School of Medicine.
authors.forename: M Wade
authors.initials: MW
authors.lastname: Calcutt
authors.affiliation: Department of Biochemistry School of Medicine.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Waterman
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: J Scott
authors.initials: JS
authors.lastname: Daniels
authors.affiliation: Antiparasitic Chemotherapy, UMR 8076 CNRS BioCIS, University Paris-Sud, Chatenay-Malabry, France.
authors.forename: Philippe M
authors.initials: PM
authors.lastname: Loiseau
authors.affiliation: Department of Microbiology and Immunology, Meharry Medical College, Nashville, Tennessee.
authors.forename: Fernando
authors.initials: F
authors.lastname: Villalta
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001549:Benzamides / Q000493:pharmacokinetics / Q000494:pharmacology*; D001711:Biotransformation; D014355:Chagas Disease / Q000188:drug therapy*; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D007898:Leishmaniasis, Visceral / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008862:Microsomes, Liver / Q000187:drug effects; D015394:Molecular Structure; D010069:Oxadiazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D014349:Trypanosoma cruzi / Q000187:drug effects
chemical_list: D000981:Antiprotozoal Agents; D001549:Benzamides; C509352:CYP51 protein, Trypanosoma cruzi; D065607:Cytochrome P-450 Enzyme Inhibitors; D007093:Imidazoles; C000604316:N-(1-(3,4'-difluorobiphenyl-4-yl)-2-(1H-imidazol-1-yl)ethyl)-4-(5-phenyl-1,3,4-oxadiazol-2-yl)benzamide; D010069:Oxadiazoles; C578921:VNI compound; D003577:Cytochrome P-450 Enzyme System
keywords: Chagas disease; Leishmania; Trypanosoma cruzi; VFV; VNI; inhibition; sterol 14α-demethylase (CYP51); sterol biosynthesis; structure-based drug design; visceral leishmaniasis