title: Clinical Candidate VT-1161's Antiparasitic Effect In Vitro, Activity in a Murine Model of Chagas Disease, and Structural Characterization in Complex with the Target Enzyme CYP51 from Trypanosoma cruzi.
abstract: A novel antifungal drug candidate, the 1-tetrazole-based agent VT-1161 [(R)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-{5-[4-(2,2,2-trifluoroethoxy)phenyl]pyridin-2-yl}propan-2-ol], which is currently in two phase 2b antifungal clinical trials, was found to be a tight-binding ligand (apparent dissociation constant [Kd], 24 nM) and a potent inhibitor of cytochrome P450 sterol 14α-demethylase (CYP51) from the protozoan pathogen Trypanosoma cruzi. Moreover, VT-1161 revealed a high level of antiparasitic activity against amastigotes of the Tulahuen strain of T. cruzi in cellular experiments (50% effective concentration, 2.5 nM) and was active in vivo, causing >99.8% suppression of peak parasitemia in a mouse model of infection with the naturally drug-resistant Y strain of the parasite. The data strongly support the potential utility of VT-1161 in the treatment of Chagas disease. The structural characterization of T. cruzi CYP51 in complex with VT-1161 provides insights into the molecular basis for the compound's inhibitory potency and paves the way for the further rational development of this novel, tetrazole-based inhibitory chemotype both for antiprotozoan chemotherapy and for antifungal chemotherapy.
authors.affiliation: Viamet Pharmaceuticals, Inc., Durham, North Carolina, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Hoekstra
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Tatiana Y
authors.initials: TY
authors.lastname: Hargrove
authors.affiliation: Synchrotron Research Center, Life Science Collaborative Access Team, Northwestern University, Argonne, Illinois, USA.
authors.forename: Zdzislaw
authors.initials: Z
authors.lastname: Wawrzak
authors.affiliation: Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
authors.forename: Denise
authors.initials: D
authors.lastname: da Gama Jaen Batista
authors.affiliation: Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
authors.forename: Cristiane F
authors.initials: CF
authors.lastname: da Silva
authors.affiliation: Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
authors.forename: Aline S G
authors.initials: AS
authors.lastname: Nefertiti
authors.affiliation: Department of Microbiology and Immunology, Meharry Medical College, Nashville, Tennessee, USA.
authors.forename: Girish
authors.initials: G
authors.lastname: Rachakonda
authors.affiliation: Viamet Pharmaceuticals, Inc., Durham, North Carolina, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Schotzinger
authors.affiliation: Department of Microbiology and Immunology, Meharry Medical College, Nashville, Tennessee, USA.
authors.forename: Fernando
authors.initials: F
authors.lastname: Villalta
authors.affiliation: Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
authors.forename: Maria de Nazaré C
authors.initials: Mde N
authors.lastname: Soeiro
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee, USA Center for Structural Biology, Vanderbilt University, Nashville, Tennessee, USA galina.i.lepesheva@vanderbilt.edu.
authors.forename: Galina I
authors.initials: GI
authors.lastname: Lepesheva
mesh_terms: D058888:14-alpha Demethylase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D014355:Chagas Disease / Q000188:drug therapy; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D005260:Female; D006418:Heme / Q000737:chemistry; D051379:Mice; D008958:Models, Molecular; D011487:Protein Conformation; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D058886:Sterol 14-Demethylase / Q000737:chemistry* / Q000378:metabolism; D013777:Tetrazoles / Q000737:chemistry / Q000494:pharmacology*; D014344:Trypanocidal Agents / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000201:enzymology
chemical_list: D058888:14-alpha Demethylase Inhibitors; D011725:Pyridines; D013777:Tetrazoles; D014344:Trypanocidal Agents; C000599187:VT-1161; D006418:Heme; D058886:Sterol 14-Demethylase