5AJR

Sterol 14-alpha demethylase (CYP51) from Trypanosoma cruzi in complex with the 1-tetrazole derivative 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)

Summary for 5AJR

• Entry DOI: 10.2210/pdb5ajr/pdb
• Descriptor: STEROL 14-ALPHA DEMETHYLASE, PROTOPORPHYRIN IX CONTAINING FE, (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 (3 entities in total)
• Functional Keywords: cytochrome p450, cyp51, oxidoreductase, monooxygenase, sterol biosynthesis, eukaryotic membranes, cytochrome p450 fold, endoplasmic reticulum membrane
• Biological source: TRYPANOSOMA CRUZI
• Cellular location: Membrane ; Single-pass membrane protein : Q7Z1V1
• Total number of polymer chains: 1
• Total formula weight: 53696.78

Authors

Wawrzak, Z.,Hoekstra, W.,I Lepesheva, G. (deposition date: 2015-02-26, release date: 2015-12-02, Last modification date: 2024-01-10)

Primary citation

Hoekstra, W.J.,Hargrove, T.Y.,Wawrzak, Z.,Da Gama Jaen Batista, D.,Da Silva, C.F.,Nefertiti, A.S.G.,Rachakonda, G.,Schotzinger, R.J.,Villalta, F.,Soeiro, M.D.N.C.,Lepesheva, G.I.
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.
Antimicrob.Agents Chemother., 60:1058-, 2015

PubMed 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.

PubMed: 26643331
DOI: 10.1128/AAC.02287-15

Experimental method

X-RAY DIFFRACTION (2.75 Å)