Mechanistic and biological characterisation of novel N 5 -substituted paullones targeting the biosynthesis of trypanothione in Leishmania .

Autor: Medeiros A; Laboratory Redox Biology of Trypanosomes, Institut Pasteur de Montevideo, Montevideo, Uruguay.; Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay., Benítez D; Laboratory Redox Biology of Trypanosomes, Institut Pasteur de Montevideo, Montevideo, Uruguay., Korn RS; Institut für Medizinische und Pharmazeutische Chemie, Technische Universität Braunschweig, Braunschweig, Germany., Ferreira VC; Instituto Gonçalo Moniz (IGM), FIOCRUZ, Salvador, Brazil., Barrera E; Biomolecular Simulations Group, Institut Pasteur de Montevideo, Montevideo, Uruguay., Carrión F; Protein Biophysics Unit, Institut Pasteur de Montevideo, Montevideo, Uruguay., Pritsch O; Protein Biophysics Unit, Institut Pasteur de Montevideo, Montevideo, Uruguay.; Departamento de Inmunobiología, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay., Pantano S; Biomolecular Simulations Group, Institut Pasteur de Montevideo, Montevideo, Uruguay., Kunick C; Institut für Medizinische und Pharmazeutische Chemie, Technische Universität Braunschweig, Braunschweig, Germany., de Oliveira CI; Instituto Gonçalo Moniz (IGM), FIOCRUZ, Salvador, Brazil., Orban OCF; Institut für Medizinische und Pharmazeutische Chemie, Technische Universität Braunschweig, Braunschweig, Germany., Comini MA; Laboratory Redox Biology of Trypanosomes, Institut Pasteur de Montevideo, Montevideo, Uruguay.
Jazyk: angličtina
Zdroj: Journal of enzyme inhibition and medicinal chemistry [J Enzyme Inhib Med Chem] 2020 Dec; Vol. 35 (1), pp. 1345-1358.
DOI: 10.1080/14756366.2020.1780227
Abstrakt: Trypanothione synthetase (TryS) produces N 1 ,N 8 -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 N 5 -substituted paullone analogues with anti-TryS activity. Several of the new derivatives retained submicromolar IC 50 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 (EC 50 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.
Databáze: MEDLINE
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