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Título:

Mechanistic and biological characterisation of novel N5-substituted paullones targeting the biosynthesis of trypanothione in Leishmania

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Autor:

Medeiros, Andrea
Benítez, Diego
Korn, Ricarda S.
Ferreira, Vinicius C.
Barrera, Exequiel
Carrión, Federico
Pritsch, Otto
Pantano, Sergio
Kunick, Conrad
de Oliveira, Camila I.
Orban, Oliver C. F.
Comini, Marcelo A.

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Artículo

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Palabras clave:

Paullone
Trypanothione synthetase
Leishmania
Thiol
Inhibition mode

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ANIMALES
QUÍMICA
BENZAZEPINAS
GLUTATIÓN
MEDICAMENTOS SIMILARES
BIOSÍNTESIS DE PROTEÍNAS
METABOLISMO
ESPERMIDINA

Año de publicación:

2020

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Resumen:

Trypanothione synthetase (TryS) produces N1,N8-bis(glutathionyl)spermidine (or trypanothione) at the expense of ATP. Trypanothione is a metabolite unique and essential for survival and drug-resistance of trypanosomatid parasites. In this study, we report the mechanistic and biological characterisation of optimised N5-substituted paullone analogues with anti-TryS activity. Several of the new derivatives retained submicromolar IC50 against leishmanial TryS. The binding mode to TryS of the most potent paullones has been revealed by means of kinetic, biophysical and molecular modelling approaches. A subset of analogues showed an improved potency (EC50 0.5–10 µM) and selectivity (20–35) against the clinically relevant stage of Leishmania braziliensis (mucocutaneous leishmaniasis) and L. infantum (visceral leishmaniasis). For a selected derivative, the mode of action involved intracellular depletion of trypanothione. Our findings shed light on the molecular interaction of TryS with rationally designed inhibitors and disclose a new set of compounds with on-target activity against different Leishmania species.

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Taylor & Francis

EN:

Journal of Enzyme Inhibition and Medicinal Chemistry. 2020;35(1):1345–1358

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Citación:

Medeiros A, Benítez D, Korn R y otros. Mechanistic and biological characterisation of novel N5-substituted paullones targeting the biosynthesis of trypanothione in Leishmania. Journal of Enzyme Inhibition and Medicinal Chemistry [en línea]. 2020;35(1):1345–1358

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Licencia Creative Commons Atribución - No Comercial (CC - By-NC 4.0)

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