Intramolecular Interactions Enhance the Potency of Gallinamide A Analogues against Trypanosoma cruzi
Autor(a) principal: | |
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Data de Publicação: | 2022 |
Outros Autores: | , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UNESP |
Texto Completo: | http://dx.doi.org/10.1021/acs.jmedchem.1c02063 http://hdl.handle.net/11449/230509 |
Resumo: | Gallinamide 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. |
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Intramolecular Interactions Enhance the Potency of Gallinamide A Analogues against Trypanosoma cruziGallinamide 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.Skaggs School of Pharmacy and Pharmaceutical Sciences Center for Discovery and Innovation in Parasitic Diseases University of California San Diego, La JollaDepartamento de Física Instituto de Biociências Letras e Ciências Exatas Universidade Estadual Paulista Julio de Mesquita Filho, São José do Rio PretoCenter for Marine Biotechnology and Biomedicine Scripps Institution of Oceanography University of California San Diego, La JollaSchool of Chemistry The University of SydneyAustralian Research Council Centre of Excellence for Innovations in Peptide and Protein Science The University of SydneyDepartamento de Física Instituto de Biociências Letras e Ciências Exatas Universidade Estadual Paulista Julio de Mesquita Filho, São José do Rio PretoUniversity of California San DiegoUniversidade Estadual Paulista (UNESP)The University of SydneyBarbosa Da Silva, ElanySharma, VandnaHernandez-Alvarez, Lilian [UNESP]Tang, Arthur H.Stoye, AlexanderO’Donoghue, Anthony J.Gerwick, William H.Payne, Richard J.McKerrow, James H.Podust, Larissa M.2022-04-29T08:40:33Z2022-04-29T08:40:33Z2022-03-10info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/article4255-4269http://dx.doi.org/10.1021/acs.jmedchem.1c02063Journal of Medicinal Chemistry, v. 65, n. 5, p. 4255-4269, 2022.1520-48040022-2623http://hdl.handle.net/11449/23050910.1021/acs.jmedchem.1c020632-s2.0-85125767378Scopusreponame:Repositório Institucional da UNESPinstname:Universidade Estadual Paulista (UNESP)instacron:UNESPengJournal of Medicinal Chemistryinfo:eu-repo/semantics/openAccess2022-04-29T08:40:33Zoai:repositorio.unesp.br:11449/230509Repositório InstitucionalPUBhttp://repositorio.unesp.br/oai/requestopendoar:29462024-08-05T20:36:39.028938Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)false |
dc.title.none.fl_str_mv |
Intramolecular Interactions Enhance the Potency of Gallinamide A Analogues against Trypanosoma cruzi |
title |
Intramolecular Interactions Enhance the Potency of Gallinamide A Analogues against Trypanosoma cruzi |
spellingShingle |
Intramolecular Interactions Enhance the Potency of Gallinamide A Analogues against Trypanosoma cruzi Barbosa Da Silva, Elany |
title_short |
Intramolecular Interactions Enhance the Potency of Gallinamide A Analogues against Trypanosoma cruzi |
title_full |
Intramolecular Interactions Enhance the Potency of Gallinamide A Analogues against Trypanosoma cruzi |
title_fullStr |
Intramolecular Interactions Enhance the Potency of Gallinamide A Analogues against Trypanosoma cruzi |
title_full_unstemmed |
Intramolecular Interactions Enhance the Potency of Gallinamide A Analogues against Trypanosoma cruzi |
title_sort |
Intramolecular Interactions Enhance the Potency of Gallinamide A Analogues against Trypanosoma cruzi |
author |
Barbosa Da Silva, Elany |
author_facet |
Barbosa Da Silva, Elany Sharma, Vandna Hernandez-Alvarez, Lilian [UNESP] Tang, Arthur H. Stoye, Alexander O’Donoghue, Anthony J. Gerwick, William H. Payne, Richard J. McKerrow, James H. Podust, Larissa M. |
author_role |
author |
author2 |
Sharma, Vandna Hernandez-Alvarez, Lilian [UNESP] Tang, Arthur H. Stoye, Alexander O’Donoghue, Anthony J. Gerwick, William H. Payne, Richard J. McKerrow, James H. Podust, Larissa M. |
author2_role |
author author author author author author author author author |
dc.contributor.none.fl_str_mv |
University of California San Diego Universidade Estadual Paulista (UNESP) The University of Sydney |
dc.contributor.author.fl_str_mv |
Barbosa Da Silva, Elany Sharma, Vandna Hernandez-Alvarez, Lilian [UNESP] Tang, Arthur H. Stoye, Alexander O’Donoghue, Anthony J. Gerwick, William H. Payne, Richard J. McKerrow, James H. Podust, Larissa M. |
description |
Gallinamide 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. |
publishDate |
2022 |
dc.date.none.fl_str_mv |
2022-04-29T08:40:33Z 2022-04-29T08:40:33Z 2022-03-10 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://dx.doi.org/10.1021/acs.jmedchem.1c02063 Journal of Medicinal Chemistry, v. 65, n. 5, p. 4255-4269, 2022. 1520-4804 0022-2623 http://hdl.handle.net/11449/230509 10.1021/acs.jmedchem.1c02063 2-s2.0-85125767378 |
url |
http://dx.doi.org/10.1021/acs.jmedchem.1c02063 http://hdl.handle.net/11449/230509 |
identifier_str_mv |
Journal of Medicinal Chemistry, v. 65, n. 5, p. 4255-4269, 2022. 1520-4804 0022-2623 10.1021/acs.jmedchem.1c02063 2-s2.0-85125767378 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Journal of Medicinal Chemistry |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
4255-4269 |
dc.source.none.fl_str_mv |
Scopus reponame:Repositório Institucional da UNESP instname:Universidade Estadual Paulista (UNESP) instacron:UNESP |
instname_str |
Universidade Estadual Paulista (UNESP) |
instacron_str |
UNESP |
institution |
UNESP |
reponame_str |
Repositório Institucional da UNESP |
collection |
Repositório Institucional da UNESP |
repository.name.fl_str_mv |
Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP) |
repository.mail.fl_str_mv |
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1808129226064265216 |