Identification of inhibitors for the transmembrane Trypanosoma cruzi eIF2α kinase relevant for parasite proliferation

Registro completo de metadados
MetadadosDescriçãoIdioma
Autor(es): dc.contributorUniversidade Federal de São Paulo (UNIFESP)-
Autor(es): dc.contributorUniversidade Estadual de Campinas (UNICAMP)-
Autor(es): dc.contributorUniversidade Estadual Paulista (UNESP)-
Autor(es): dc.contributorBIOCEV-
Autor(es): dc.contributorUniversity of Dundee-
Autor(es): dc.contributorCzech Academy of Sciences-
Autor(es): dc.contributorUniversidade Federal de Minas Gerais (UFMG)-
Autor(es): dc.creatorMarcelino, Tiago de Paula-
Autor(es): dc.creatorFala, Angela Maria-
Autor(es): dc.creatorda Silva, Matheus Monteiro-
Autor(es): dc.creatorSouza-Melo, Normanda-
Autor(es): dc.creatorMalvezzi, Amaranta Muniz-
Autor(es): dc.creatorKlippel, Angélica Hollunder-
Autor(es): dc.creatorZoltner, Martin-
Autor(es): dc.creatorPadilla-Mejia, Norma-
Autor(es): dc.creatorKosto, Samantha-
Autor(es): dc.creatorField, Mark C.-
Autor(es): dc.creatorBurle-Caldas, Gabriela de Assis-
Autor(es): dc.creatorTeixeira, Santuza Maria Ribeiro-
Autor(es): dc.creatorCouñago, Rafael Miguez-
Autor(es): dc.creatorMassirer, Katlin Brauer-
Autor(es): dc.creatorSchenkman, Sergio-
Data de aceite: dc.date.accessioned2025-08-21T16:42:52Z-
Data de disponibilização: dc.date.available2025-08-21T16:42:52Z-
Data de envio: dc.date.issued2025-04-29-
Data de envio: dc.date.issued2023-07-01-
Fonte completa do material: dc.identifierhttp://dx.doi.org/10.1016/j.jbc.2023.104857-
Fonte completa do material: dc.identifierhttps://hdl.handle.net/11449/297940-
Fonte: dc.identifier.urihttp://educapes.capes.gov.br/handle/11449/297940-
Descrição: dc.descriptionThe TcK2 protein kinase of Trypanosoma cruzi, the causative agent of Chagas disease, is structurally similar to the human kinase PERK, which phosphorylates the initiation factor eIF2α and, in turn, inhibits translation initiation. We have previously shown that absence of TcK2 kinase impairs parasite proliferation within mammalian cells, positioning it as a potential target for treatment of Chagas disease. To better understand its role in the parasite, here we initially confirmed the importance of TcK2 in parasite proliferation by generating CRISPR/Cas9 TcK2-null cells, albeit they more efficiently differentiate into infective forms. Proteomics indicates that the TcK2 knockout of proliferative forms expresses proteins including trans-sialidases, normally restricted to infective and nonproliferative trypomastigotes explaining decreased proliferation and better differentiation. TcK2 knockout cells lost phosphorylation of eukaryotic initiation factor 3 and cyclic AMP responsive-like element, recognized to promote growth, likely explaining both decreased proliferation and augmented differentiation. To identify specific inhibitors, a library of 379 kinase inhibitors was screened by differential scanning fluorimetry using a recombinant TcK2 encompassing the kinase domain and selected molecules were tested for kinase inhibition. Only Dasatinib and PF-477736, inhibitors of Src/Abl and ChK1 kinases, showed inhibitory activity with IC50 of 0.2 ± 0.02 mM and 0.8 ± 0.1, respectively. In infected cells Dasatinib inhibited growth of parental amastigotes (IC50 = 0.6 ± 0.2 mM) but not TcK2 of depleted parasites (IC50 > 34 mM) identifying Dasatinib as a potential lead for development of therapeutics for Chagas disease targeting TcK2.-
Descrição: dc.descriptionFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)-
Descrição: dc.descriptionDepartamento de Microbiologia Imunologia e Parasitologia Escola Paulista de Medicina Universidade Federal de São Paulo, SP-
Descrição: dc.descriptionCenter for Molecular Biology and Genetic Engineering – CBMEG Center of Medicinal Chemistry - CQMED Structural Genomics Consortium - SGC University of Campinas - UNICAMP, SP-
Descrição: dc.descriptionDepartamento de Ciências Biológicas da Faculdade de Ciências Farmacêuticas da Universidade Estadual Paulista “Júlio de Mesquita Filho”-Unesp, SP-
Descrição: dc.descriptionDrug Discovery and Evaluation Unit Department of Parasitology Faculty of Science Charles University in Prague BIOCEV-
Descrição: dc.descriptionSchool of Life Sciences University of Dundee-
Descrição: dc.descriptionBiology Centre Institute of Parasitology Czech Academy of Sciences-
Descrição: dc.descriptionDepartamento de Bioquímica e Imunologia Universidade Federal de Minas Gerais, MG-
Descrição: dc.descriptionDepartamento de Ciências Biológicas da Faculdade de Ciências Farmacêuticas da Universidade Estadual Paulista “Júlio de Mesquita Filho”-Unesp, SP-
Idioma: dc.languageen-
Relação: dc.relationJournal of Biological Chemistry-
???dc.source???: dc.sourceScopus-
Palavras-chave: dc.subjectchagas disease-
Palavras-chave: dc.subjectchemical inhibitor-
Palavras-chave: dc.subjecteIF2α-
Palavras-chave: dc.subjectinvasion-
Palavras-chave: dc.subjectprotein kinase-
Palavras-chave: dc.subjectproteome-
Palavras-chave: dc.subjectrecombinant protein-
Palavras-chave: dc.subjectT.cruzi EIF2AK2-
Título: dc.titleIdentification of inhibitors for the transmembrane Trypanosoma cruzi eIF2α kinase relevant for parasite proliferation-
Tipo de arquivo: dc.typelivro digital-
Aparece nas coleções:Repositório Institucional - Unesp

Não existem arquivos associados a este item.