Structure-Aided Computational Design of Triazole-Based Targeted Covalent Inhibitors of Cruzipain
- Autores
- Cerutti, Juan Pablo; Abreu Diniz, Lucas; Corrêa Santos, Viviane; Vilchez Larrea, Salomé Catalina; Alonso, Guillermo Daniel; Salgado Ferreira, Rafaela; Dehaen, Wim; Quevedo, Mario Alfredo
- Año de publicación
- 2024
- Idioma
- inglés
- Tipo de recurso
- artículo
- Estado
- versión publicada
- Descripción
- Cruzipain (CZP), the major cysteine protease present in T. cruzi, the ethiological agent of Chagas disease, has attracted particular attention as a therapeutic target for the development of targeted covalent inhibitors (TCI). The vast chemical space associated with the enormous molecular diversity feasible to explore by means of modern synthetic approaches allows the design of CZP inhibitors capable of exhibiting not only an efficient enzyme inhibition but also an adequate translation to anti-T. cruzi activity. In this work, a computer-aided design strategy was developed to combinatorially construct and screen large libraries of 1,4-disubstituted 1,2,3-triazole analogues, further identifying a selected set of candidates for advancement towards synthetic and biological activity evaluation stages. In this way, a virtual molecular library comprising more than 75 thousand diverse and synthetically feasible analogues was studied by means of molecular docking and molecular dynamic simulations in the search of potential TCI of CZP, guiding the synthetic efforts towards a subset of 48 candidates. These were synthesized by applying a Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) centered synthetic scheme, resulting in moderate to good yields and leading to the identification of 12 hits selectively inhibiting CZP activity with IC50 in the low micromolar range. Furthermore, four triazole derivatives showed good anti-T. cruzi inhibition when studied at 50 µM; and Ald-6 excelled for its high antitrypanocidal activity and low cytotoxicity, exhibiting complete in vitro biological activity translation from CZP to T. cruzi. Overall, not only Ald-6 merits further advancement to preclinical in vivo studies, but these findings also shed light on a valuable chemical space where molecular diversity might be explored in the search for efficient triazole-based antichagasic agents.
Fil: Cerutti, Juan Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica; Argentina. Katholikie Universiteit Leuven; Bélgica
Fil: Abreu Diniz, Lucas. Universidade Do Estado de Mina Gerais;
Fil: Corrêa Santos, Viviane. Universidade Do Estado de Mina Gerais;
Fil: Vilchez Larrea, Salomé Catalina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Universidad de Buenos Aires; Argentina
Fil: Alonso, Guillermo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Salgado Ferreira, Rafaela. Universidade Do Estado de Mina Gerais;
Fil: Dehaen, Wim. Katholikie Universiteit Leuven; Bélgica
Fil: Quevedo, Mario Alfredo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica; Argentina - Materia
-
Chagas
Cruzipaina - Nivel de accesibilidad
- acceso abierto
- Condiciones de uso
- https://creativecommons.org/licenses/by/2.5/ar/
- Repositorio
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/262240
Ver los metadatos del registro completo
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Structure-Aided Computational Design of Triazole-Based Targeted Covalent Inhibitors of CruzipainCerutti, Juan PabloAbreu Diniz, LucasCorrêa Santos, VivianeVilchez Larrea, Salomé CatalinaAlonso, Guillermo DanielSalgado Ferreira, RafaelaDehaen, WimQuevedo, Mario AlfredoChagasCruzipainahttps://purl.org/becyt/ford/1.4https://purl.org/becyt/ford/1Cruzipain (CZP), the major cysteine protease present in T. cruzi, the ethiological agent of Chagas disease, has attracted particular attention as a therapeutic target for the development of targeted covalent inhibitors (TCI). The vast chemical space associated with the enormous molecular diversity feasible to explore by means of modern synthetic approaches allows the design of CZP inhibitors capable of exhibiting not only an efficient enzyme inhibition but also an adequate translation to anti-T. cruzi activity. In this work, a computer-aided design strategy was developed to combinatorially construct and screen large libraries of 1,4-disubstituted 1,2,3-triazole analogues, further identifying a selected set of candidates for advancement towards synthetic and biological activity evaluation stages. In this way, a virtual molecular library comprising more than 75 thousand diverse and synthetically feasible analogues was studied by means of molecular docking and molecular dynamic simulations in the search of potential TCI of CZP, guiding the synthetic efforts towards a subset of 48 candidates. These were synthesized by applying a Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) centered synthetic scheme, resulting in moderate to good yields and leading to the identification of 12 hits selectively inhibiting CZP activity with IC50 in the low micromolar range. Furthermore, four triazole derivatives showed good anti-T. cruzi inhibition when studied at 50 µM; and Ald-6 excelled for its high antitrypanocidal activity and low cytotoxicity, exhibiting complete in vitro biological activity translation from CZP to T. cruzi. Overall, not only Ald-6 merits further advancement to preclinical in vivo studies, but these findings also shed light on a valuable chemical space where molecular diversity might be explored in the search for efficient triazole-based antichagasic agents.Fil: Cerutti, Juan Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica; Argentina. Katholikie Universiteit Leuven; BélgicaFil: Abreu Diniz, Lucas. Universidade Do Estado de Mina Gerais;Fil: Corrêa Santos, Viviane. Universidade Do Estado de Mina Gerais;Fil: Vilchez Larrea, Salomé Catalina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Universidad de Buenos Aires; ArgentinaFil: Alonso, Guillermo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Salgado Ferreira, Rafaela. Universidade Do Estado de Mina Gerais;Fil: Dehaen, Wim. Katholikie Universiteit Leuven; BélgicaFil: Quevedo, Mario Alfredo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica; ArgentinaMolecular Diversity Preservation International2024-09info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/262240Cerutti, Juan Pablo; Abreu Diniz, Lucas; Corrêa Santos, Viviane; Vilchez Larrea, Salomé Catalina; Alonso, Guillermo Daniel; et al.; Structure-Aided Computational Design of Triazole-Based Targeted Covalent Inhibitors of Cruzipain; Molecular Diversity Preservation International; Molecules; 29; 17; 9-2024; 1-241420-3049CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.mdpi.com/1420-3049/29/17/4224info:eu-repo/semantics/altIdentifier/doi/10.3390/molecules29174224info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T10:09:27Zoai:ri.conicet.gov.ar:11336/262240instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-03 10:09:27.964CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse |
dc.title.none.fl_str_mv |
Structure-Aided Computational Design of Triazole-Based Targeted Covalent Inhibitors of Cruzipain |
title |
Structure-Aided Computational Design of Triazole-Based Targeted Covalent Inhibitors of Cruzipain |
spellingShingle |
Structure-Aided Computational Design of Triazole-Based Targeted Covalent Inhibitors of Cruzipain Cerutti, Juan Pablo Chagas Cruzipaina |
title_short |
Structure-Aided Computational Design of Triazole-Based Targeted Covalent Inhibitors of Cruzipain |
title_full |
Structure-Aided Computational Design of Triazole-Based Targeted Covalent Inhibitors of Cruzipain |
title_fullStr |
Structure-Aided Computational Design of Triazole-Based Targeted Covalent Inhibitors of Cruzipain |
title_full_unstemmed |
Structure-Aided Computational Design of Triazole-Based Targeted Covalent Inhibitors of Cruzipain |
title_sort |
Structure-Aided Computational Design of Triazole-Based Targeted Covalent Inhibitors of Cruzipain |
dc.creator.none.fl_str_mv |
Cerutti, Juan Pablo Abreu Diniz, Lucas Corrêa Santos, Viviane Vilchez Larrea, Salomé Catalina Alonso, Guillermo Daniel Salgado Ferreira, Rafaela Dehaen, Wim Quevedo, Mario Alfredo |
author |
Cerutti, Juan Pablo |
author_facet |
Cerutti, Juan Pablo Abreu Diniz, Lucas Corrêa Santos, Viviane Vilchez Larrea, Salomé Catalina Alonso, Guillermo Daniel Salgado Ferreira, Rafaela Dehaen, Wim Quevedo, Mario Alfredo |
author_role |
author |
author2 |
Abreu Diniz, Lucas Corrêa Santos, Viviane Vilchez Larrea, Salomé Catalina Alonso, Guillermo Daniel Salgado Ferreira, Rafaela Dehaen, Wim Quevedo, Mario Alfredo |
author2_role |
author author author author author author author |
dc.subject.none.fl_str_mv |
Chagas Cruzipaina |
topic |
Chagas Cruzipaina |
purl_subject.fl_str_mv |
https://purl.org/becyt/ford/1.4 https://purl.org/becyt/ford/1 |
dc.description.none.fl_txt_mv |
Cruzipain (CZP), the major cysteine protease present in T. cruzi, the ethiological agent of Chagas disease, has attracted particular attention as a therapeutic target for the development of targeted covalent inhibitors (TCI). The vast chemical space associated with the enormous molecular diversity feasible to explore by means of modern synthetic approaches allows the design of CZP inhibitors capable of exhibiting not only an efficient enzyme inhibition but also an adequate translation to anti-T. cruzi activity. In this work, a computer-aided design strategy was developed to combinatorially construct and screen large libraries of 1,4-disubstituted 1,2,3-triazole analogues, further identifying a selected set of candidates for advancement towards synthetic and biological activity evaluation stages. In this way, a virtual molecular library comprising more than 75 thousand diverse and synthetically feasible analogues was studied by means of molecular docking and molecular dynamic simulations in the search of potential TCI of CZP, guiding the synthetic efforts towards a subset of 48 candidates. These were synthesized by applying a Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) centered synthetic scheme, resulting in moderate to good yields and leading to the identification of 12 hits selectively inhibiting CZP activity with IC50 in the low micromolar range. Furthermore, four triazole derivatives showed good anti-T. cruzi inhibition when studied at 50 µM; and Ald-6 excelled for its high antitrypanocidal activity and low cytotoxicity, exhibiting complete in vitro biological activity translation from CZP to T. cruzi. Overall, not only Ald-6 merits further advancement to preclinical in vivo studies, but these findings also shed light on a valuable chemical space where molecular diversity might be explored in the search for efficient triazole-based antichagasic agents. Fil: Cerutti, Juan Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica; Argentina. Katholikie Universiteit Leuven; Bélgica Fil: Abreu Diniz, Lucas. Universidade Do Estado de Mina Gerais; Fil: Corrêa Santos, Viviane. Universidade Do Estado de Mina Gerais; Fil: Vilchez Larrea, Salomé Catalina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Universidad de Buenos Aires; Argentina Fil: Alonso, Guillermo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina Fil: Salgado Ferreira, Rafaela. Universidade Do Estado de Mina Gerais; Fil: Dehaen, Wim. Katholikie Universiteit Leuven; Bélgica Fil: Quevedo, Mario Alfredo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica; Argentina |
description |
Cruzipain (CZP), the major cysteine protease present in T. cruzi, the ethiological agent of Chagas disease, has attracted particular attention as a therapeutic target for the development of targeted covalent inhibitors (TCI). The vast chemical space associated with the enormous molecular diversity feasible to explore by means of modern synthetic approaches allows the design of CZP inhibitors capable of exhibiting not only an efficient enzyme inhibition but also an adequate translation to anti-T. cruzi activity. In this work, a computer-aided design strategy was developed to combinatorially construct and screen large libraries of 1,4-disubstituted 1,2,3-triazole analogues, further identifying a selected set of candidates for advancement towards synthetic and biological activity evaluation stages. In this way, a virtual molecular library comprising more than 75 thousand diverse and synthetically feasible analogues was studied by means of molecular docking and molecular dynamic simulations in the search of potential TCI of CZP, guiding the synthetic efforts towards a subset of 48 candidates. These were synthesized by applying a Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) centered synthetic scheme, resulting in moderate to good yields and leading to the identification of 12 hits selectively inhibiting CZP activity with IC50 in the low micromolar range. Furthermore, four triazole derivatives showed good anti-T. cruzi inhibition when studied at 50 µM; and Ald-6 excelled for its high antitrypanocidal activity and low cytotoxicity, exhibiting complete in vitro biological activity translation from CZP to T. cruzi. Overall, not only Ald-6 merits further advancement to preclinical in vivo studies, but these findings also shed light on a valuable chemical space where molecular diversity might be explored in the search for efficient triazole-based antichagasic agents. |
publishDate |
2024 |
dc.date.none.fl_str_mv |
2024-09 |
dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion http://purl.org/coar/resource_type/c_6501 info:ar-repo/semantics/articulo |
format |
article |
status_str |
publishedVersion |
dc.identifier.none.fl_str_mv |
http://hdl.handle.net/11336/262240 Cerutti, Juan Pablo; Abreu Diniz, Lucas; Corrêa Santos, Viviane; Vilchez Larrea, Salomé Catalina; Alonso, Guillermo Daniel; et al.; Structure-Aided Computational Design of Triazole-Based Targeted Covalent Inhibitors of Cruzipain; Molecular Diversity Preservation International; Molecules; 29; 17; 9-2024; 1-24 1420-3049 CONICET Digital CONICET |
url |
http://hdl.handle.net/11336/262240 |
identifier_str_mv |
Cerutti, Juan Pablo; Abreu Diniz, Lucas; Corrêa Santos, Viviane; Vilchez Larrea, Salomé Catalina; Alonso, Guillermo Daniel; et al.; Structure-Aided Computational Design of Triazole-Based Targeted Covalent Inhibitors of Cruzipain; Molecular Diversity Preservation International; Molecules; 29; 17; 9-2024; 1-24 1420-3049 CONICET Digital CONICET |
dc.language.none.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
info:eu-repo/semantics/altIdentifier/url/https://www.mdpi.com/1420-3049/29/17/4224 info:eu-repo/semantics/altIdentifier/doi/10.3390/molecules29174224 |
dc.rights.none.fl_str_mv |
info:eu-repo/semantics/openAccess https://creativecommons.org/licenses/by/2.5/ar/ |
eu_rights_str_mv |
openAccess |
rights_invalid_str_mv |
https://creativecommons.org/licenses/by/2.5/ar/ |
dc.format.none.fl_str_mv |
application/pdf application/pdf application/pdf |
dc.publisher.none.fl_str_mv |
Molecular Diversity Preservation International |
publisher.none.fl_str_mv |
Molecular Diversity Preservation International |
dc.source.none.fl_str_mv |
reponame:CONICET Digital (CONICET) instname:Consejo Nacional de Investigaciones Científicas y Técnicas |
reponame_str |
CONICET Digital (CONICET) |
collection |
CONICET Digital (CONICET) |
instname_str |
Consejo Nacional de Investigaciones Científicas y Técnicas |
repository.name.fl_str_mv |
CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas |
repository.mail.fl_str_mv |
dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar |
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1842270081748303872 |
score |
13.13397 |