Novel Selective and Low-Toxic Inhibitor of LmCPB2.8ΔCTE (CPB) One Important Cysteine Protease for Leishmania Virulence

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Autor(es): dc.contributorUniversidade Estadual Paulista (UNESP)-
Autor(es): dc.contributorUniversity of Vienna-
Autor(es): dc.contributorFederal University of Rio de Janeiro-
Autor(es): dc.contributorParacelsus Medical University-
Autor(es): dc.creatorMoreira, Vitor Partite-
Autor(es): dc.creatorda Silva Mela, Michele Ferreira-
Autor(es): dc.creatorAnjos, Luana Ribeiro dos-
Autor(es): dc.creatorSaraiva, Leonardo Figueiredo-
Autor(es): dc.creatorArenas Velásquez, Angela M.-
Autor(es): dc.creatorKalaba, Predrag-
Autor(es): dc.creatorFabisiková, Anna-
Autor(es): dc.creatorClementino, Leandro da Costa-
Autor(es): dc.creatorAufy, Mohammed-
Autor(es): dc.creatorStudenik, Christian-
Autor(es): dc.creatorGajic, Natalie-
Autor(es): dc.creatorPrado-Roller, Alexander-
Autor(es): dc.creatorMagalhães, Alvicler-
Autor(es): dc.creatorZehl, Martin-
Autor(es): dc.creatorFigueiredo, Ingrid Delbone-
Autor(es): dc.creatorBaviera, Amanda Martins-
Autor(es): dc.creatorCilli, Eduardo Maffud-
Autor(es): dc.creatorGraminha, Marcia A. S.-
Autor(es): dc.creatorLubec, Gert-
Autor(es): dc.creatorGonzalez, Eduardo R. Perez-
Data de aceite: dc.date.accessioned2025-08-21T21:31:42Z-
Data de disponibilização: dc.date.available2025-08-21T21:31:42Z-
Data de envio: dc.date.issued2023-07-29-
Data de envio: dc.date.issued2023-07-29-
Data de envio: dc.date.issued2022-11-30-
Fonte completa do material: dc.identifierhttp://dx.doi.org/10.3390/biom12121903-
Fonte completa do material: dc.identifierhttp://hdl.handle.net/11449/248064-
Fonte: dc.identifier.urihttp://educapes.capes.gov.br/handle/11449/248064-
Descrição: dc.descriptionLeishmaniasis is a highly prevalent, yet neglected disease caused by protozoan parasites of the genus Leishmania. In the search for newer, safer, and more effective antileishmanial compounds, we herein present a study of the mode of action in addition to a detailed structural and biological characterization of LQOF-G6 [N-benzoyl-N′-benzyl-N″-(4-tertbutylphenyl)guanidine]. X-ray crystallography and extensive NMR experiments revealed that LQOF-G6 nearly exclusively adopts the Z conformation stabilized by an intramolecular hydrogen bond. The investigated guanidine showed selective inhibitory activity on Leishmania major cysteine protease LmCPB2.8ΔCTE (CPB) with ~73% inhibition and an IC50-CPB of 6.0 µM. This compound did not show any activity against the mammalian homologues cathepsin L and B. LQOF-G6 has been found to be nontoxic toward both organs and several cell lines, and no signs of hepatotoxicity or nephrotoxicity were observed from the analysis of biochemical clinical plasma markers in the treated mice. Docking simulations and experimental NMR measurements showed a clear contribution of the conformational parameters to the strength of the binding in the active site of the enzyme, and thus fit the differences in the inhibition values of LQOF-G6 compared to the other guanidines. Furthermore, the resulting data render LQOF-G6 suitable for further development as an antileishmanial drug.-
Descrição: dc.descriptionFine Organic Chemistry Lab School of Sciences and Technology São Paulo State University (UNESP)-
Descrição: dc.descriptionSchool of Pharmaceutical Sciences São Paulo State University (UNESP)-
Descrição: dc.descriptionLaboratory of Luminescence in Materials and Sensors School of Sciences and Technology São Paulo State University (UNESP)-
Descrição: dc.descriptionDepartment of Pharmaceutical Sciences Division of Pharmaceutical Chemistry Faculty of Life Sciences University of Vienna, Josef Holaubek Platz 2, UZAII-
Descrição: dc.descriptionMass Spectrometry Centre Faculty of Chemistry University of Vienna, Währinger Straße 38-
Descrição: dc.descriptionDepartment of Pharmaceutical Sciences Division of Pharmacology and Toxicology University of Vienna, Josef Holaubek Platz 2, UZAII (2D 259)-
Descrição: dc.descriptionCentre for X-ray Structure Analysis Faculty of Chemistry University of Vienna, Währinger Straße 40-42-
Descrição: dc.descriptionDepartment of Organic Chemistry Chemistry School Federal University of Rio de Janeiro-
Descrição: dc.descriptionDepartment of Analytical Chemistry Faculty of Chemistry University of Vienna, Währinger Straße 38-
Descrição: dc.descriptionDepartment of Biochemistry and Organic Chemistry Institute of Chemistry São Paulo State University (UNESP)-
Descrição: dc.descriptionDepartment of Neuroproteomics Paracelsus Medical University-
Descrição: dc.descriptionFine Organic Chemistry Lab School of Sciences and Technology São Paulo State University (UNESP)-
Descrição: dc.descriptionSchool of Pharmaceutical Sciences São Paulo State University (UNESP)-
Descrição: dc.descriptionLaboratory of Luminescence in Materials and Sensors School of Sciences and Technology São Paulo State University (UNESP)-
Descrição: dc.descriptionDepartment of Biochemistry and Organic Chemistry Institute of Chemistry São Paulo State University (UNESP)-
Idioma: dc.languageen-
Relação: dc.relationBiomolecules-
???dc.source???: dc.sourceScopus-
Palavras-chave: dc.subjectguanidines-
Palavras-chave: dc.subjectLeishmania cysteine protease inhibition-
Palavras-chave: dc.subjectleishmanicidal activity-
Palavras-chave: dc.subjectmolecular docking-
Palavras-chave: dc.subjectX-ray and NMR conformational study-
Título: dc.titleNovel Selective and Low-Toxic Inhibitor of LmCPB2.8ΔCTE (CPB) One Important Cysteine Protease for Leishmania Virulence-
Tipo de arquivo: dc.typelivro digital-
Aparece nas coleções:Repositório Institucional - Unesp

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