Identification of Novel Chemical Scaffolds Inhibiting Trypanothione Synthetase from Pathogenic Trypanosomatids

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Identification of Novel Chemical Scaffolds Inhibiting Trypanothione Synthetase from Pathogenic Trypanosomatids

Tema

TRIPANOSOMAS
ENZIMAS
BIBLIOGRAFIA NACIONAL QUIMICA
2016

Abstract

BACKGROUND: The search for novel chemical entities targeting essential and parasite-specific pathways is considered a priority for neglected diseases such as trypanosomiasis and leishmaniasis. The thiol-dependent redox metabolism of trypanosomatids relies on bis-glutathionylspermidine [trypanothione, T(SH)2], a low molecular mass cosubstrate absent in the host. In pathogenic trypanosomatids, a single enzyme, trypanothione synthetase (TryS), catalyzes trypanothione biosynthesis, which is indispensable for parasite survival. Thus, TryS qualifies as an attractive drug target candidate. METHODOLOGY/PRINCIPAL FINDING: A library composed of 144 compounds from 7 different families and several singletons was screened against TryS from three major pathogen species (Trypanosoma brucei, Trypanosoma cruzi and Leishmania infantum). The screening conditions were adjusted to the TryS´ kinetic parameters and intracellular concentration of substrates corresponding to each trypanosomatid species, and/or to avoid assay interference. The screening assay yielded suitable Z' and signal to noise values (≥0.85 and ~3.5, respectively), and high intra-assay reproducibility. Several novel chemical scaffolds were identified as low μM and selective tri-tryp TryS inhibitors. Compounds displaying multi-TryS inhibition (N,N'-bis(3,4-substituted-benzyl) diamine derivatives) and an N5-substituted paullone (MOL2008) halted the proliferation of infective Trypanosoma brucei (EC50 in the nM range) and Leishmania infantum promastigotes (EC50 = 12 μM), respectively. A bis-benzyl diamine derivative and MOL2008 depleted intracellular trypanothione in treated parasites, which confirmed the on-target activity of these compounds. CONCLUSIONS/SIGNIFICANCE: Novel molecular scaffolds with on-target mode of action were identified as hit candidates for TryS inhibition. Due to the remarkable species-specificity exhibited by tri-tryp TryS towards the compounds, future optimization and screening campaigns should aim at designing and detecting, respectively, more potent and broad-range TryS inhibitors.

Autor

Benítez, D.
Medeiros, A.
Fiestas, L.
Panozzo-Zenere, E.A.
Maiwald, F.
Prousis, K.C.
Roussaki, M.
Calogeropoulou, T.
Detsi, A.
Jaeger, T.
Šarlauskas, J.
Peterlin Mašic, L.
Kunick, C.
Labadie, G.R.
Flohé, L.
Comini, M.A.

Fuente

PLoS Neglected Tropical Diseases v. 10, no. 4, 2016. -- 25p. e0004617

Editor

Plos One

Fecha

2016

Derechos

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PDF

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Tipo

Artículo

Identificador

DOI: 10.1371/journal.pntd.0004617

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PDF
Fecha de agregación
June 23, 2017
Colección
Bibliografía Nacional Química
Tipo de Elemento
Document
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Citación
Benítez, D., “Identification of Novel Chemical Scaffolds Inhibiting Trypanothione Synthetase from Pathogenic Trypanosomatids,” RIQUIM - Repositorio Institucional de la Facultad de Química - UdelaR, accessed October 3, 2022, http://riquim.fq.edu.uy/items/show/4627.
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