Clinical Candidate VT-1161's Antiparasitic EffectIn Vitro, Activity in a Murine Model of Chagas Disease, and Structural Characterization in Complex with the Target Enzyme CYP51 from Trypanosoma cruzi

Hoekstra, William J.; Hargrove, Tatiana Y.; Wawrzak, Zdzislaw; da Gama Jaen Batista, Denise; da Silva, Cristiane F.; Nefertiti, Aline G.; Rachakonda, Girish; Schotzinger, Robert J.; Villalta, Fernando; Soeiro, Maria C.; Lepesheva, Galina I.

doi:10.1128/aac.02287-15

Title: Clinical Candidate VT-1161's Antiparasitic EffectIn Vitro, Activity in a Murine Model of Chagas Disease, and Structural Characterization in Complex with the Target Enzyme CYP51 from Trypanosoma cruzi

Journal Article · Mon Dec 07 00:00:00 EST 2015 · Antimicrobial Agents and Chemotherapy

DOI:https://doi.org/10.1128/aac.02287-15· OSTI ID:1236886

Hoekstra, William J. ^[1]; Hargrove, Tatiana Y. ^[2]; Wawrzak, Zdzislaw ^[3]; da Gama Jaen Batista, Denise ^[4]; da Silva, Cristiane F. ^[4]; Nefertiti, Aline G. ^[4]; Rachakonda, Girish ^[5]; Schotzinger, Robert J. ^[1]; Villalta, Fernando ^[5]; Soeiro, Maria C. ^[4]; Lepesheva, Galina I. ^[2]

Viamet Pharmaceuticals, Inc., Durham, NC (United States)
Vanderbilt Univ., Nashville, TN (United States)
Northwestern Univ., Evanston, IL (United States)
Instituto Oswaldo Cruz (Brazil)
Meharry Medical College, Nashville, TN (United States)

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 [K_d], 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.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: AC02- 06CH11357; GM067871; MD007593

OSTI ID:: 1236886

Journal Information:: Antimicrobial Agents and Chemotherapy, Vol. 60, Issue 2; ISSN 0066-4804

Publisher:: American Society for MicrobiologyCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 30 works

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Advances in preclinical approaches to Chagas disease drug discovery Villalta, Fernando; Rachakonda, Girish Expert Opinion on Drug Discovery, Vol. 14, Issue 11 https://doi.org/10.1080/17460441.2019.1652593	journal	July 2019
Discovery and Genetic Validation of Chemotherapeutic Targets for Chagas' Disease Osorio-Méndez, Juan Felipe; Cevallos, Ana María Frontiers in Cellular and Infection Microbiology, Vol. 8 https://doi.org/10.3389/fcimb.2018.00439	journal	January 2019
Structural analyses of Candida albicans sterol 14α-demethylase complexed with azole drugs address the molecular basis of azole-mediated inhibition of fungal sterol biosynthesis Hargrove, Tatiana Y.; Friggeri, Laura; Wawrzak, Zdzislaw Journal of Biological Chemistry, Vol. 292, Issue 16 https://doi.org/10.1074/jbc.m117.778308	journal	March 2017
Chagas disease research and development: Is there light at the end of the tunnel? Chatelain, Eric Computational and Structural Biotechnology Journal, Vol. 15 https://doi.org/10.1016/j.csbj.2016.12.002	journal	January 2017
Repurposing of terconazole as an anti Trypanosoma cruzi agent Reigada, Chantal; Sayé, Melisa; Valera-Vera, Edward Heliyon, Vol. 5, Issue 6 https://doi.org/10.1016/j.heliyon.2019.e01947	journal	June 2019
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