期刊论文详细信息
Journal of Enzyme Inhibition and Medicinal Chemistry
Mechanistic and biological characterisation of novel N5-substituted paullones targeting the biosynthesis of trypanothione in Leishmania
Sergio Pantano1  Exequiel Barrera1  Oliver C. F. Orban2  Conrad Kunick2  Ricarda S. Korn2  Vinicius C. Ferreira3  Camila I. de Oliveira3  Andrea Medeiros4  Marcelo A. Comini4  Diego Benítez4  Federico Carrión5  Otto Pritsch5 
[1] Biomolecular Simulations Group, Institut Pasteur de Montevideo;Institut für Medizinische und Pharmazeutische Chemie, Technische Universität Braunschweig;Instituto Gonçalo Moniz (IGM), FIOCRUZ;Laboratory Redox Biology of Trypanosomes, Institut Pasteur de Montevideo;Protein Biophysics Unit, Institut Pasteur de Montevideo;
关键词: paullone;    trypanothione synthetase;    leishmania;    thiol;    inhibition mode;   
DOI  :  10.1080/14756366.2020.1780227
来源: DOAJ
【 摘 要 】

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.

【 授权许可】

Unknown   

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