Pyrrole-indolinone SU11652 targets the nucleoside diphosphate kinase from Leishmania parasites

Autor(es):Mostrar menos -

Vieira, Plinio Salmazo ; Campos Brasil Souza, Tatiana de Arruda ; Honorato, Rodrigo Vargas ; Zanphorlin, Leticia Maria ; Severiano, Kelven Ulisses ; Rocco, Silvana Aparecida ; Cavalcante de Oliveira, Arthur Henrique ; Cordeiro, Artur Torres ; Lopes Oliveira, Paulo Sergio ; de Giuseppe, Priscila Oliveira ; Murakami, Mario Tyago

• Tipo de documento: Artigo Científico
• Fonte: Biochemical and Biophysical Research Communications; v. 488, n. 3, p. 461-465, JUL 1 2017.
• Citações Web of Science: 3

Resumo

Nucleoside diphosphate kinases (NDKs) are key enzymes in the purine-salvage pathway of trypanosomatids and have been associated with the maintenance of host-cell integrity for the benefit of the parasite, being potential targets for rational drug discovery and design. The NDK from Leishmania major (LmNDK) and mutants were expressed and purified to homogeneity. Thermal shift assays were employed to identify potential inhibitors for LmNDK. Calorimetric experiments, site-directed mutagenesis and molecular docking analysis were performed to validate the interaction and to evaluate the structural basis of ligand recognition. Furthermore, the anti-leishmanial activity of the newly identified and validated compound was tested in vitro against different Leishmania species. The molecule SU11652, a Sunitinib analog, was identified as a potential inhibitor for LmNDK and structural studies indicated that this molecule binds to the active site of LmNDK in a similar conformation to nucleotides, mimicking natural substrates. Isothermal titration calorimetry experiments combined with site-directed mutagenesis revealed that the residues H50 and H117, considered essential for catalysis, play an important role in ligand binding. In vitro cell studies showed that SU11652 had similar efficacy to Amphotericin b against some Leishmania species. Together, our results indicate the pyrrole-indolinone SU11652 as a promising scaffold for the rational design of new drugs targeting the enzyme NDK from Leishmania parasites. (C) 2017 Elsevier Inc. All rights reserved. (AU)

• Processo FAPESP: 11/20569-2 - Papel de aminoácidos do sítio ativo e da interface oligomérica na estrutura e função da nucleosídeo difosfato kinase de Leishmania major
• Beneficiário: Arthur Henrique Cavalcante de Oliveira
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 10/03761-4 - Caracterização cinética e efeito de mutações na interface oligomérica da Nucleosídeo Difosfato Kinase de Leishmania major.
• Beneficiário: Plínio Salmazo Vieira
• Modalidade de apoio: Bolsas no Brasil - Mestrado
• Processo FAPESP: 07/06755-2 - Caracterização estrutural e funcional de proteínas envolvidas na virulência do protozoário parasita Leishmania major
• Beneficiário: Arthur Henrique Cavalcante de Oliveira
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 11/24178-8 - Estudos estruturais das NEK quinases de Leishmania braziliensis.
• Beneficiário: Plínio Salmazo Vieira
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 10/51730-0 - SMolBNet 2.0: estudos funcionais e estruturais de proteína-cinases envolvidas em câncer e doenças negligenciadas, visando ao desenvolvimento de novos inibidores
• Beneficiário: Jörg Kobarg
• Modalidade de apoio: Auxílio à Pesquisa - Regular