| Author | Medeiros, Andrea | |
| Author | Benítez, Diego | |
| Author | Korn, Ricarda S. | |
| Author | Ferreira, Vinicius C. | |
| Author | Barrera, Exequiel | |
| Author | Carrión, Federico | |
| Author | Pritsch, Otto | |
| Author | Pantano, Sergio | |
| Author | Kunick, Conrad | |
| Author | Oliveira, Camila Indiani de | |
| Author | Orban, Oliver C. F. | |
| Author | Comini, Marcelo A. | |
| Access date | 2020-07-17T12:22:43Z | |
| Available date | 2020-07-17T12:22:43Z | |
| Document date | 2020 | |
| Citation | MEDEIROS, Andrea et al. Mechanistic and biological characterisation of novel N5-substituted paullones targeting the biosynthesis of trypanothione in Leishmania. Journal of Enzyme Inhibition and Medicinal Chemistry, v. 35, n. 1, p. 1345–1358, 2020. | pt_BR |
| ISSN | 1475-6366 | pt_BR |
| URI | https://www.arca.fiocruz.br/handle/icict/42289 | |
| Sponsorship | Agencia Nacional de
Investigaci on e Innovaci on (ANII, Uruguay) under grant
POS_NAC_2013_1_114477; Comisi on Sectorial de Investigaci on
Cient ıfica (CSIC), Universidad de la Rep ublica Uruguay under grant
Nr. 3404; Fondo para la Convergencia Estructural del MERCOSUR
(Mercado Com un del Sur) under grant FOCEM; Institut Pasteur
Paris under grant ACIP 17–2015; European Cooperation in Science
and Technology (COST) under grant CM1307; German
Bundesministerium f€ur Bildung und Forschung (KMUinnovativ 5)
under grant 0315814; Deutsche Forschungsgemeinschaft (DFG)
under grant KU 1371/9-1. | pt_BR |
| Language | eng | pt_BR |
| Publisher | Taylor & Francis Open | pt_BR |
| Rights | open access | pt_BR |
| Subject in Portuguese | Leishmania | pt_BR |
| Subject in Portuguese | Trypanosoma | pt_BR |
| Subject in Portuguese | Resistência a medicamentos | pt_BR |
| Title | Mechanistic and biological characterisation of novel N5-substituted paullones targeting the biosynthesis of trypanothione in Leishmania | pt_BR |
| Type | Article | pt_BR |
| DOI | 10.1080/14756366.2020.1780227 | |
| Abstract | 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. | pt_BR |
| Affilliation | Institut Pasteur de Montevideo. Laboratory Redox Biology of Trypanosomes. Montevideo, Uruguay / Universidad de la Republica. Facultad de Medicina. Departamento de Bioquimica. Montevideo, Uruguay. | pt_BR |
| Affilliation | Institut Pasteur de Montevideo. Laboratory Redox Biology of Trypanosomes. Montevideo, Uruguay. | pt_BR |
| Affilliation | Technische Universitat Braunschweig. Institut f€ur Medizinische und Pharmazeutische Chemie. Braunschweig, Germany. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil. | pt_BR |
| Affilliation | Institut Pasteur de Montevideo. Biomolecular Simulations Group. Montevideo, Uruguay. | pt_BR |
| Affilliation | Institut Pasteur de Montevideo. Protein Biophysics Unit. Montevideo, Uruguay / Universidad de la Republica. Facultad de Medicina. Departamento de Inmunobiologıa. Montevideo, Uruguay. | pt_BR |
| Affilliation | Institut Pasteur de Montevideo. Biomolecular Simulations Group. Montevideo, Uruguay. | pt_BR |
| Affilliation | Technische Universitat Braunschweig. Institut f€ur Medizinische und Pharmazeutische Chemie. Braunschweig, Germany. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil. | pt_BR |
| Affilliation | Technische Universitat Braunschweig. Institut f€ur Medizinische und Pharmazeutische Chemie. Braunschweig, Germany. | pt_BR |
| Affilliation | Institut Pasteur de Montevideo. Laboratory Redox Biology of Trypanosomes. Montevideo, Uruguay. | pt_BR |
| Subject | Paullone | pt_BR |
| Subject | Trypanothione synthetase | pt_BR |
| Subject | Leishmania | pt_BR |
| Subject | Thiol | pt_BR |
| Subject | Drug Resistance | pt_BR |
| Subject | Inhibition mode | pt_BR |
| xmlui.metadata.dc.subject.ods | 03 Saúde e Bem-Estar | |
