TY - JOUR
T1 - 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
AU - Hoekstra, William J.
AU - Hargrove, Tatiana Y.
AU - Wawrzak, Zdzislaw
AU - Da Gama Jaen Batista, Denise
AU - Da Silva, Cristiane F.
AU - Nefertiti, Aline S.G.
AU - Rachakonda, Girish
AU - Schotzinger, Robert J.
AU - Villalta, Fernando
AU - Soeiro, Maria De Nazaré C.
AU - Lepesheva, Galina I.
N1 - Funding Information:
This work was supported by Viamet Pharmaceuticals, Inc. (Durham, NC), and in part by National Institutes of Health grant R01 GM067871 (to G.I.L.). Vanderbilt University is a member institution of the Life Science Collaborative Team (LS-CAT) at Sector 21 of the Advanced Photon Source (APS), Argonne, IL. Use of the APS at Argonne National Laboratory was supported by the United States Department of Energy, Office of Science, Office of Basic Energy Sciences, under contract no. DE-AC02- 06CH11357. The use of LS-CAT Sector 21 was supported by the Michigan Economic Development Corporation and the Michigan Technology Tri- Corridor (grant 085P1000817). The use of the Confocal Microscopy Facility at Meharry Medical College was supported by MD007593 (to F.V.). M.D.N.C.S. is research fellow of CNPq and CNE (FAPERJ).
Publisher Copyright:
Copyright © 2016, American Society for Microbiology. All Rights Reserved.
PY - 2016/2
Y1 - 2016/2
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84957922138&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84957922138&partnerID=8YFLogxK
U2 - 10.1128/AAC.02287-15
DO - 10.1128/AAC.02287-15
M3 - Article
C2 - 26643331
AN - SCOPUS:84957922138
VL - 60
SP - 1058
EP - 1066
JO - Antimicrobial Agents and Chemotherapy
JF - Antimicrobial Agents and Chemotherapy
SN - 0066-4804
IS - 2
ER -