Intramolecular Interactions Enhance the Potency of Gallinamide A Analogues against Trypanosoma cruzi

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Autor(es): dc.contributorUniversity of California San Diego-
Autor(es): dc.contributorUniversidade Estadual Paulista (UNESP)-
Autor(es): dc.contributorThe University of Sydney-
Autor(es): dc.creatorBarbosa Da Silva, Elany-
Autor(es): dc.creatorSharma, Vandna-
Autor(es): dc.creatorHernandez-Alvarez, Lilian-
Autor(es): dc.creatorTang, Arthur H.-
Autor(es): dc.creatorStoye, Alexander-
Autor(es): dc.creatorO’Donoghue, Anthony J.-
Autor(es): dc.creatorGerwick, William H.-
Autor(es): dc.creatorPayne, Richard J.-
Autor(es): dc.creatorMcKerrow, James H.-
Autor(es): dc.creatorPodust, Larissa M.-
Data de aceite: dc.date.accessioned2025-08-21T20:42:38Z-
Data de disponibilização: dc.date.available2025-08-21T20:42:38Z-
Data de envio: dc.date.issued2022-04-29-
Data de envio: dc.date.issued2022-04-29-
Data de envio: dc.date.issued2022-03-10-
Fonte completa do material: dc.identifierhttp://dx.doi.org/10.1021/acs.jmedchem.1c02063-
Fonte completa do material: dc.identifierhttp://hdl.handle.net/11449/230509-
Fonte: dc.identifier.urihttp://educapes.capes.gov.br/handle/11449/230509-
Descrição: dc.descriptionGallinamide A, a metabolite of the marine cyanobacterium Schizothrix sp., selectively inhibits cathepsin L-like cysteine proteases. We evaluated the potency of gallinamide A and 23 synthetic analogues against intracellular Trypanosoma cruzi amastigotes and the cysteine protease, cruzain. We determined the co-crystal structures of cruzain with gallinamide A and two synthetic analogues at ∼2 Å. SAR data revealed that the N-terminal end of gallinamide A is loosely bound and weakly contributes in drug-target interactions. At the C-terminus, the intramolecular π-π stacking interactions between the aromatic substituents at P1′ and P1 restrict the bioactive conformation of the inhibitors, thus minimizing the entropic loss associated with target binding. Molecular dynamics simulations showed that in the absence of an aromatic group at P1, the substituent at P1′ interacts with tryptophan-184. The P1-P1′ interactions had no effect on anti-cruzain activity, whereas anti-T. cruzi potency increased by ∼fivefold, likely due to an increase in solubility/permeability of the analogues.-
Descrição: dc.descriptionSkaggs School of Pharmacy and Pharmaceutical Sciences Center for Discovery and Innovation in Parasitic Diseases University of California San Diego, La Jolla-
Descrição: dc.descriptionDepartamento de Física Instituto de Biociências Letras e Ciências Exatas Universidade Estadual Paulista Julio de Mesquita Filho, São José do Rio Preto-
Descrição: dc.descriptionCenter for Marine Biotechnology and Biomedicine Scripps Institution of Oceanography University of California San Diego, La Jolla-
Descrição: dc.descriptionSchool of Chemistry The University of Sydney-
Descrição: dc.descriptionAustralian Research Council Centre of Excellence for Innovations in Peptide and Protein Science The University of Sydney-
Descrição: dc.descriptionDepartamento de Física Instituto de Biociências Letras e Ciências Exatas Universidade Estadual Paulista Julio de Mesquita Filho, São José do Rio Preto-
Formato: dc.format4255-4269-
Idioma: dc.languageen-
Relação: dc.relationJournal of Medicinal Chemistry-
???dc.source???: dc.sourceScopus-
Título: dc.titleIntramolecular Interactions Enhance the Potency of Gallinamide A Analogues against Trypanosoma cruzi-
Tipo de arquivo: dc.typelivro digital-
Aparece nas coleções:Repositório Institucional - Unesp

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