Sterol 14α-Demethylase Structure-Based Optimization of Drug Candidates for Human Infections with the Protozoan Trypanosomatidae

Laura Friggeri; Tatiana Y. Hargrove; Girish Rachakonda; Anna L. Blobaum; Paxtyn Fisher; Gabriel Melo De Oliveira; Cristiane França Da Silva; Maria De Nazaré C. Soeiro; W. David Nes; Craig W. Lindsley; Fernando Villalta; F. Peter Guengerich; Galina I. Lepesheva

doi:10.1021/acs.jmedchem.8b01671

Sterol 14α-Demethylase Structure-Based Optimization of Drug Candidates for Human Infections with the Protozoan Trypanosomatidae

Laura Friggeri, Tatiana Y. Hargrove, Girish Rachakonda, Anna L. Blobaum, Paxtyn Fisher, Gabriel Melo De Oliveira, Cristiane França Da Silva, Maria De Nazaré C. Soeiro, W. David Nes, Craig W. Lindsley, Fernando Villalta, F. Peter Guengerich, Galina I. Lepesheva

Chemistry and Biochemistry

Research output: Contribution to journal › Article

5 Scopus citations

Abstract

Sterol 14α-demethylases (CYP51) are cytochrome P450 enzymes essential for sterol biosynthesis in eukaryotes and therapeutic targets for antifungal azoles. Multiple attempts to repurpose antifungals for treatment of human infections with protozoa (Trypanosomatidae) have been undertaken, yet so far none of them have revealed sufficient efficacy. VNI and its derivative VFV are two potent experimental inhibitors of Trypanosomatidae CYP51, effective in vivo against Chagas disease, visceral leishmaniasis, and sleeping sickness and currently under consideration as antiprotozoal drug candidates. However, VNI is less potent against Leishmania and drug-resistant strains of Trypanosoma cruzi and VFV, while displaying a broader spectrum of antiprotozoal activity, and is metabolically less stable. In this work we have designed, synthesized, and characterized a set of close analogues and identified two new compounds (7 and 9) that exceed VNI/VFV in their spectra of antiprotozoal activity, microsomal stability, and pharmacokinetics (tissue distribution in particular) and, like VNI/VFV, reveal no acute toxicity.

Original language	English
Pages (from-to)	10910-10921
Number of pages	12
Journal	Journal of Medicinal Chemistry
Volume	61
Issue number	23
DOIs	https://doi.org/10.1021/acs.jmedchem.8b01671
State	Published - Dec 13 2018

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Friggeri, L., Hargrove, T. Y., Rachakonda, G., Blobaum, A. L., Fisher, P., De Oliveira, G. M., Da Silva, C. F., Soeiro, M. D. N. C., Nes, W. D., Lindsley, C. W., Villalta, F., Guengerich, F. P., & Lepesheva, G. I. (2018). Sterol 14α-Demethylase Structure-Based Optimization of Drug Candidates for Human Infections with the Protozoan Trypanosomatidae. Journal of Medicinal Chemistry, 61(23), 10910-10921. https://doi.org/10.1021/acs.jmedchem.8b01671

Friggeri, Laura ; Hargrove, Tatiana Y. ; Rachakonda, Girish ; Blobaum, Anna L. ; Fisher, Paxtyn ; De Oliveira, Gabriel Melo ; Da Silva, Cristiane França ; Soeiro, Maria De Nazaré C. ; Nes, W. David ; Lindsley, Craig W. ; Villalta, Fernando ; Guengerich, F. Peter ; Lepesheva, Galina I. / Sterol 14α-Demethylase Structure-Based Optimization of Drug Candidates for Human Infections with the Protozoan Trypanosomatidae. In: Journal of Medicinal Chemistry. 2018 ; Vol. 61, No. 23. pp. 10910-10921.

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title = "Sterol 14α-Demethylase Structure-Based Optimization of Drug Candidates for Human Infections with the Protozoan Trypanosomatidae",

abstract = "Sterol 14α-demethylases (CYP51) are cytochrome P450 enzymes essential for sterol biosynthesis in eukaryotes and therapeutic targets for antifungal azoles. Multiple attempts to repurpose antifungals for treatment of human infections with protozoa (Trypanosomatidae) have been undertaken, yet so far none of them have revealed sufficient efficacy. VNI and its derivative VFV are two potent experimental inhibitors of Trypanosomatidae CYP51, effective in vivo against Chagas disease, visceral leishmaniasis, and sleeping sickness and currently under consideration as antiprotozoal drug candidates. However, VNI is less potent against Leishmania and drug-resistant strains of Trypanosoma cruzi and VFV, while displaying a broader spectrum of antiprotozoal activity, and is metabolically less stable. In this work we have designed, synthesized, and characterized a set of close analogues and identified two new compounds (7 and 9) that exceed VNI/VFV in their spectra of antiprotozoal activity, microsomal stability, and pharmacokinetics (tissue distribution in particular) and, like VNI/VFV, reveal no acute toxicity.",

author = "Laura Friggeri and Hargrove, {Tatiana Y.} and Girish Rachakonda and Blobaum, {Anna L.} and Paxtyn Fisher and {De Oliveira}, {Gabriel Melo} and {Da Silva}, {Cristiane Fran{\c c}a} and Soeiro, {Maria De Nazar{\'e} C.} and Nes, {W. David} and Lindsley, {Craig W.} and Fernando Villalta and Guengerich, {F. Peter} and Lepesheva, {Galina I.}",

year = "2018",

month = dec,

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doi = "10.1021/acs.jmedchem.8b01671",

language = "English",

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Friggeri, L, Hargrove, TY, Rachakonda, G, Blobaum, AL, Fisher, P, De Oliveira, GM, Da Silva, CF, Soeiro, MDNC, Nes, WD, Lindsley, CW, Villalta, F, Guengerich, FP & Lepesheva, GI 2018, 'Sterol 14α-Demethylase Structure-Based Optimization of Drug Candidates for Human Infections with the Protozoan Trypanosomatidae', Journal of Medicinal Chemistry, vol. 61, no. 23, pp. 10910-10921. https://doi.org/10.1021/acs.jmedchem.8b01671

Sterol 14α-Demethylase Structure-Based Optimization of Drug Candidates for Human Infections with the Protozoan Trypanosomatidae. / Friggeri, Laura; Hargrove, Tatiana Y.; Rachakonda, Girish; Blobaum, Anna L.; Fisher, Paxtyn; De Oliveira, Gabriel Melo; Da Silva, Cristiane França; Soeiro, Maria De Nazaré C.; Nes, W. David; Lindsley, Craig W.; Villalta, Fernando; Guengerich, F. Peter; Lepesheva, Galina I.

In: Journal of Medicinal Chemistry, Vol. 61, No. 23, 13.12.2018, p. 10910-10921.

Research output: Contribution to journal › Article

TY - JOUR

T1 - Sterol 14α-Demethylase Structure-Based Optimization of Drug Candidates for Human Infections with the Protozoan Trypanosomatidae

AU - Friggeri, Laura

AU - Hargrove, Tatiana Y.

AU - Rachakonda, Girish

AU - Blobaum, Anna L.

AU - Fisher, Paxtyn

AU - De Oliveira, Gabriel Melo

AU - Da Silva, Cristiane França

AU - Soeiro, Maria De Nazaré C.

AU - Nes, W. David

AU - Lindsley, Craig W.

AU - Villalta, Fernando

AU - Guengerich, F. Peter

AU - Lepesheva, Galina I.

PY - 2018/12/13

Y1 - 2018/12/13

N2 - Sterol 14α-demethylases (CYP51) are cytochrome P450 enzymes essential for sterol biosynthesis in eukaryotes and therapeutic targets for antifungal azoles. Multiple attempts to repurpose antifungals for treatment of human infections with protozoa (Trypanosomatidae) have been undertaken, yet so far none of them have revealed sufficient efficacy. VNI and its derivative VFV are two potent experimental inhibitors of Trypanosomatidae CYP51, effective in vivo against Chagas disease, visceral leishmaniasis, and sleeping sickness and currently under consideration as antiprotozoal drug candidates. However, VNI is less potent against Leishmania and drug-resistant strains of Trypanosoma cruzi and VFV, while displaying a broader spectrum of antiprotozoal activity, and is metabolically less stable. In this work we have designed, synthesized, and characterized a set of close analogues and identified two new compounds (7 and 9) that exceed VNI/VFV in their spectra of antiprotozoal activity, microsomal stability, and pharmacokinetics (tissue distribution in particular) and, like VNI/VFV, reveal no acute toxicity.

AB - Sterol 14α-demethylases (CYP51) are cytochrome P450 enzymes essential for sterol biosynthesis in eukaryotes and therapeutic targets for antifungal azoles. Multiple attempts to repurpose antifungals for treatment of human infections with protozoa (Trypanosomatidae) have been undertaken, yet so far none of them have revealed sufficient efficacy. VNI and its derivative VFV are two potent experimental inhibitors of Trypanosomatidae CYP51, effective in vivo against Chagas disease, visceral leishmaniasis, and sleeping sickness and currently under consideration as antiprotozoal drug candidates. However, VNI is less potent against Leishmania and drug-resistant strains of Trypanosoma cruzi and VFV, while displaying a broader spectrum of antiprotozoal activity, and is metabolically less stable. In this work we have designed, synthesized, and characterized a set of close analogues and identified two new compounds (7 and 9) that exceed VNI/VFV in their spectra of antiprotozoal activity, microsomal stability, and pharmacokinetics (tissue distribution in particular) and, like VNI/VFV, reveal no acute toxicity.

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U2 - 10.1021/acs.jmedchem.8b01671

DO - 10.1021/acs.jmedchem.8b01671

M3 - Article

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AN - SCOPUS:85058147150

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