Clinical Candidate VT-1161's Antiparasitic Effect
            <i>In Vitro</i>
            , 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, Z.; Batista, Denise da Gama Jaén; Silva, Cristiane F. da; Nefertiti, A. S. G.; Rachakonda, Girish; Schotzinger, Robert J.; Villalta, Fernando; Soeiro, Maria de Nazaré Correia; Lepesheva, Galina I.

doi:10.1128/aac.02287-15

Cited by 38 publications

(24 citation statements)

References 53 publications

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“…The length of the Fe-N coordination bond is 2.1 Å in the posaconazole complex and 2.2 Å in the VT-1161 complex, reflecting the higher basicity of the N4 atom in the 1,2,4-triazole ring of posaconazole in comparison with the N4 atom in the 1,2,3,4-tetrazole ring in VT-1161 (38) and supporting higher selectivity (39) of VT-1161 toward the target CYP51 enzymes versus human "drug-metabolizing" P450s (28). This result also corresponds to the shorter red shift (39) induced by VT-1161 in the C. albicans CYP51 Soret band maximum (417-421 nm versus 417-423 nm in the case of posaconazole (see Fig.…”

Section: Structural Analysismentioning

confidence: 99%

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

Friggeri

Wawrzak

et al. 2017

Journal of Biological Chemistry

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284

277

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With some advances in modern medicine (such as cancer chemotherapy, broad exposure to antibiotics, and immunosuppression), the incidence of opportunistic fungal pathogens such as has increased. Cases of drug resistance among these pathogens have become more frequent, requiring the development of new drugs and a better understanding of the targeted enzymes. Sterol 14α-demethylase (CYP51) is a cytochrome P450 enzyme required for biosynthesis of sterols in eukaryotic cells and is the major target of clinical drugs for managing fungal pathogens, but some of the CYP51 key features important for rational drug design have remained obscure. We report the catalytic properties, ligand-binding profiles, and inhibition of enzymatic activity of CYP51 by clinical antifungal drugs that are used systemically (fluconazole, voriconazole, ketoconazole, itraconazole, and posaconazole) and topically (miconazole and clotrimazole) and by a tetrazole-based drug candidate, VT-1161 (oteseconazole: ()-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1-tetrazol-1-yl)-1-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-ol). Among the compounds tested, the first-line drug fluconazole was the weakest inhibitor, whereas posaconazole and VT-1161 were the strongest CYP51 inhibitors. We determined the X-ray structures of CYP51 complexes with posaconazole and VT-1161, providing a molecular mechanism for the potencies of these drugs, including the activity of VT-1161 against and , pathogens that are intrinsically resistant to fluconazole. Our comparative structural analysis outlines phylum-specific CYP51 features that could direct future rational development of more efficient broad-spectrum antifungals.

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Section: Structural Analysismentioning

confidence: 99%

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

Friggeri

Wawrzak

et al. 2017

Journal of Biological Chemistry

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284

277

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“…In the absence of a clear-cut answer, some efforts aimed at developing T . cruzi specific CYP51 inhibitors are still being considered [55], [56]. These studies have also highlighted a lack of sound interpretation of scientific rationale, shown how difficult it is to break dogma and the importance of an integrated research pipeline to speed up the delivery of future Chagas disease treatment candidates.…”

Section: Chagas Disease Drug Discovery and Development: A Very Dynamimentioning

confidence: 99%

Chagas disease research and development: Is there light at the end of the tunnel?

Chatelain

2017

Computational and Structural Biotechnology Journal

130

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Chagas disease, or American trypanosomiasis, is the result of infection by the parasite Trypanosoma cruzi. It is endemic in Latin America, and spreading around the globe due to human migration. Although it was first identified more than a century ago, only two old drugs are available for treatment and a lot of questions related to the disease progression, its pathologies, and not to mention the assessment of treatment efficacy, are subject to debate and remain to be answered. Indeed, the current status of evidence and data available does not allow any absolute statement related to treatment needs and outcome for Chagas patients to be made. Although there has been some new impetus in Research and Development for Chagas disease following recent new clinical trials, there is a scientific requirement to review and challenge the current status of evidence and define basic and clinical research priorities and next steps in the field. This should ensure that the best drugs for Chagas disease are developed, but will require a focused and collaborative effort of the entire Chagas disease research community.

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“…The crystal structures of C. albicans LDM (N-truncCaLDM6ϫHis) have been determined for complexes with PCZ and VT-1161 (14). The crystal structure of the Trypanosoma cruzi CYP51B catalytic domain in complex with VT-1161 has also been determined (15). VT-1161 shows tight type II binding to CaLDM and C. neoformans LDM and binds weakly to HsCYP51 (16,17).…”

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confidence: 99%

Crystal Structures of Full-Length Lanosterol 14α-Demethylases of Prominent Fungal Pathogens Candida albicans and Candida glabrata Provide Tools for Antifungal Discovery

Keniya

Sabherwal

Wilson

et al. 2018

Antimicrob Agents Chemother

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Targeting lanosterol 14α-demethylase (LDM) with azole drugs provides prophylaxis and treatments for superficial and disseminated fungal infections, but cure rates are not optimal for immunocompromised patients and individuals with comorbidities. The efficacy of azole drugs has also been reduced due to the emergence of drug-resistant fungal pathogens. We have addressed the need to improve the potency, spectrum, and specificity for azoles by expressing in functional, recombinant, hexahistidine-tagged, full-length LDM (CaLDM6×His) and LDM (CgLDM6×His) and determining their X-ray crystal structures. The crystal structures of CaLDM6×His, CgLDM6×His, and ScLDM6×His have the same fold and bind itraconazole in nearly identical conformations. The catalytic domains of the full-length LDMs have the same fold as the CaLDM6×His catalytic domain in complex with posaconazole, with minor structural differences within the ligand binding pocket. Our structures give insight into the LDM reaction mechanism and phenotypes of single-site CaLDM mutations. This study provides a practical basis for the structure-directed discovery of novel antifungals that target LDMs of fungal pathogens.

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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

Cited by 38 publications

References 53 publications

Structural analyses of Candida albicans sterol 14α-demethylase complexed with azole drugs address the molecular basis of azole-mediated inhibition of fungal sterol biosynthesis

Structural analyses of Candida albicans sterol 14α-demethylase complexed with azole drugs address the molecular basis of azole-mediated inhibition of fungal sterol biosynthesis

Chagas disease research and development: Is there light at the end of the tunnel?

Crystal Structures of Full-Length Lanosterol 14α-Demethylases of Prominent Fungal Pathogens Candida albicans and Candida glabrata Provide Tools for Antifungal Discovery

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