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AutorChoy, Jonathan W.
AutorBryant, Clifford
AutorCalvet, Claudia M.
AutorDoyle, Patrícia S.
AutorGunatilleke, Shamila S.
AutorLeung, Siegfried S. F.
AutorAng, Kenny K. H.
AutorChen, Steven
AutorGut, Jiri
AutorOses-Prieto, Juan A.
AutorJohnston, Jonathan B.
AutorArkin, Michelle R.
AutorBurlingame, Alma L.
AutorTaunton, Jack
AutorJacobson, Matthew P.
AutorMcKerrow, James F.
AutorPodust, Larissa M.
AutorRenslo, Adam R.
Fecha de acceso2015-09-21T17:25:48Z
Fecha de disponibilización2015-09-21T17:25:48Z
Fecha de publicación2013
ReferenciaCHOY, Jonathan W. et al. Chemical–biological characterization of a cruzain inhibitor reveals a second target and a mammalian off-target. Beilstein Journal of Organic Chemistry, v. 9, p. 15–25, 2013.pt_BR
ISSN1860-5397pt_BR
URIhttps://www.arca.fiocruz.br/handle/icict/11786
Idiomaengpt_BR
EditorBeilstein-Institutpt_BR
Derechos de autoropen access
TítuloChemical–biological characterization of a cruzain inhibitor reveals a second target and a mammalian off-targetpt_BR
Tipo del documentoArticle
DOI10.3762/bjoc.9.3pt_BR
Resumen en InglésInhibition of the Trypanosoma cruzi cysteine protease cruzain has been proposed as a therapeutic approach for the treatment of Chagas’ disease. Among the best-studied cruzain inhibitors to date is the vinylsulfone K777 (1), which has proven effective in animal models of Chagas’ disease. Recent structure–activity studies aimed at addressing potential liabilities of 1 have now produced analogues such as N-[(2S)-1-[[(E,3S)-1-(benzenesulfonyl)-5-phenylpent-1-en-3-yl]amino]-3-(4-methylphenyl)-1-oxopropan-2-yl]pyridine-4-carboxamide (4), which is trypanocidal at ten-fold lower concentrations than for 1. We now find that the trypanocidal activity of 4 derives primarily from the inhibition of T. cruzi 14-α-demethylase (TcCYP51), a cytochrome P450 enzyme involved in the biosynthesis of ergosterol in the parasite. Compound 4 also inhibits mammalian CYP isoforms but is trypanocidal at concentrations below those required to significantly inhibit mammalian CYPs in vitro. A chemical-proteomics approach employing an activity-based probe derived from 1 was used to identify mammalian cathepsin B as a potentially important off-target of 1 and 4. Computational docking studies and the evaluation of truncated analogues of 4 reveal structural determinants for TcCYP51 binding, information that will be useful in further optimization of this new class of inhibitors.pt_BR
AfiliaciónUniversity of California San Francisco. Small Molecule Discovery Center. Department of Pharmaceutical Chemistry. Department of Cellular and Molecular Pharmacology. San Francisco, CA, USA.pt_BR
AfiliaciónUniversity of California San Francisco. Small Molecule Discovery Center. Department of Pharmaceutical Chemistry. San Francisco, CA, USA.pt_BR
AfiliaciónUniversity of California San Francisco. Center for Discovery and Innovation in Parasitic Diseases. Department of Pathology. San Francisco, CA, USA / Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Ultraestrutura Celular. Rio de Janeiro, RJ, Brasil.pt_BR
AfiliaciónUniversity of California San Francisco. Center for Discovery and Innovation in Parasitic Diseases. Department of Pathology. San Francisco, CA, USA.pt_BR
AfiliaciónUniversity of California San Francisco. Center for Discovery and Innovation in Parasitic Diseases. Department of Pathology. San Francisco, CA, USA.pt_BR
AfiliaciónUniversity of California San Francisco. Department of Pharmaceutical Chemistry. San Francisco, CA. USA.pt_BR
AfiliaciónUniversity of California San Francisco. Small Molecule Discovery Center. Department of Pharmaceutical Chemistry. San Francisco, CA, USA.pt_BR
AfiliaciónUniversity of California San Francisco. Small Molecule Discovery Center. Department of Pharmaceutical Chemistry. San Francisco, CA, USA.pt_BR
AfiliaciónUniversity of California San Francisco. Center for Discovery and Innovation in Parasitic Diseases. Department of Pathology. San Francisco, CA, USA.pt_BR
AfiliaciónUniversity of California San Francisco. Department of Pharmaceutical Chemistry. San Francisco, CA. USA.pt_BR
AfiliaciónUniversity of California San Francisco. Department of Pharmaceutical Chemistry. San Francisco, CA. USA.pt_BR
AfiliaciónUniversity of California San Francisco. Small Molecule Discovery Center. Department of Pharmaceutical Chemistry. Center for Discovery and Innovation in Parasitic Diseases. San Francisco, CA, USA.pt_BR
AfiliaciónUniversity of California San Francisco. Department of Pharmaceutical Chemistry. San Francisco, CA. USA.pt_BR
AfiliaciónUniversity of California San Francisco. Department of Cellular and Molecular Pharmacology. San Francisco, CA, USA.pt_BR
AfiliaciónUniversity of California San Francisco. Department of Pharmaceutical Chemistry. San Francisco, CA. USA.pt_BR
AfiliaciónUniversity of California San Francisco. Center for Discovery and Innovation in Parasitic Diseases. Department of Pathology. San Francisco, CA, USA.pt_BR
AfiliaciónUniversity of California San Francisco. Center for Discovery and Innovation in Parasitic Diseases. Department of Pathology. San Francisco, CA, USA.pt_BR
AfiliaciónUniversity of California San Francisco. Small Molecule Discovery Center. Department of Pharmaceutical Chemistry. Center for Discovery and Innovation in Parasitic Diseases. San Francisco, CA, USA.pt_BR
Palavras clave en InglêsActivity-based probespt_BR
Palavras clave en InglêsChagas diseasept_BR
Palavras clave en InglêsCruzainpt_BR
Palavras clave en InglêsCYP51pt_BR
Palavras clave en InglêsHybrid drugspt_BR
Palavras clave en InglêsTrypanosoma cruzipt_BR
DeCSTrypanosoma cruzipt_BR
DeCSDoença de Chagaspt_BR


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