Mechanistic and biological characterisation of novel N5-substituted paullones targeting the biosynthesis of trypanothione in Leishmania. (1st January 2020)

• Record Type: Journal Article
• Authors: 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.
• Is Part Of: Journal of enzyme inhibition and medicinal chemistry. Volume 35:Number 1(2020)
• Page Start: 1345
• Page End: 1358
• Publication Date: 2020-01-01
• Subjects: Paullone -- trypanothione synthetase -- Leishmania -- thiol -- inhibition mode; Enzyme inhibitors -- Periodicals; Enzyme Inhibitors -- periodicals; Biochemistry -- periodicals; 572.7
• DOI: 10.1080/14756366.2020.1780227
• Languages: English
• ISSNs: 1475-6366

Abstract

Abstract: 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 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.