High-throughput prioritization of target proteins for development of new antileishmanial compounds

Autores
Azevedo, Lucas G.; Sosa, Ezequiel; de Queiroz, Artur T. L.; Barral, Aldina; Wheeler, Richard J.; Nicolás, Marisa F.; Farias, Leonardo P.; Fernández Do Porto, Darío Augusto; Ramos, Pablo Ivan P.
Año de publicación
2024
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Leishmaniasis, a vector-borne disease, is caused by the infection of Leishmania spp., obligate intracellular protozoan parasites. Presently, human vaccines are unavailable, and the primary treatment relies heavily on systemic drugs, often presenting with suboptimal formulations and substantial toxicity, making new drugs a high priority for LMIC countries burdened by the disease, but a low priority in the agenda of most pharmaceutical companies due to unattractive profit margins. New ways to accelerate the discovery of new, or the repositioning of existing drugs, are needed. To address this challenge, our study aimed to identify potential protein targets shared among clinically-relevant Leishmania species. We employed a subtractive proteomics and comparative genomics approach, integrating high-throughput multi-omics data to classify these targets based on different druggability metrics. This effort resulted in the ranking of 6502 ortholog groups of protein targets across 14 pathogenic Leishmania species. Among the top 20 highly ranked groups, metabolic processes known to be attractive drug targets, including the ubiquitination pathway, aminoacyl-tRNA synthetases, and purine synthesis, were rediscovered. Additionally, we unveiled novel promising targets such as the nicotinate phosphoribosyltransferase enzyme and dihydrolipoamide succinyltransferases. These groups exhibited appealing druggability features, including less than 40% sequence identity to the human host proteome, predicted essentiality, structural classification as highly druggable or druggable, and expression levels above the 50th percentile in the amastigote form. The resources presented in this work also represent a comprehensive collection of integrated data regarding trypanosomatid biology.
Fil: Azevedo, Lucas G.. Instituto Oswaldo Cruz; Brasil
Fil: Sosa, Ezequiel. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina
Fil: de Queiroz, Artur T. L.. Instituto Oswaldo Cruz; Brasil
Fil: Barral, Aldina. Ministerio de Salud de Brasil; Brasil
Fil: Wheeler, Richard J.. University of Oxford; Reino Unido
Fil: Nicolás, Marisa F.. Laboratorio Nacional de Computacao Cientifica; Brasil
Fil: Farias, Leonardo P.. Instituto Oswaldo Cruz; Brasil
Fil: Fernández Do Porto, Darío Augusto. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Calculo. - Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Calculo; Argentina
Fil: Ramos, Pablo Ivan P.. Instituto Oswaldo Cruz; Brasil
Materia
leishmania
drug targets
drug discovery
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/258746
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/258746
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling High-throughput prioritization of target proteins for development of new antileishmanial compoundsAzevedo, Lucas G.Sosa, Ezequielde Queiroz, Artur T. L.Barral, AldinaWheeler, Richard J.Nicolás, Marisa F.Farias, Leonardo P.Fernández Do Porto, Darío AugustoRamos, Pablo Ivan P.leishmaniadrug targetsdrug discoveryhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Leishmaniasis, a vector-borne disease, is caused by the infection of Leishmania spp., obligate intracellular protozoan parasites. Presently, human vaccines are unavailable, and the primary treatment relies heavily on systemic drugs, often presenting with suboptimal formulations and substantial toxicity, making new drugs a high priority for LMIC countries burdened by the disease, but a low priority in the agenda of most pharmaceutical companies due to unattractive profit margins. New ways to accelerate the discovery of new, or the repositioning of existing drugs, are needed. To address this challenge, our study aimed to identify potential protein targets shared among clinically-relevant Leishmania species. We employed a subtractive proteomics and comparative genomics approach, integrating high-throughput multi-omics data to classify these targets based on different druggability metrics. This effort resulted in the ranking of 6502 ortholog groups of protein targets across 14 pathogenic Leishmania species. Among the top 20 highly ranked groups, metabolic processes known to be attractive drug targets, including the ubiquitination pathway, aminoacyl-tRNA synthetases, and purine synthesis, were rediscovered. Additionally, we unveiled novel promising targets such as the nicotinate phosphoribosyltransferase enzyme and dihydrolipoamide succinyltransferases. These groups exhibited appealing druggability features, including less than 40% sequence identity to the human host proteome, predicted essentiality, structural classification as highly druggable or druggable, and expression levels above the 50th percentile in the amastigote form. The resources presented in this work also represent a comprehensive collection of integrated data regarding trypanosomatid biology.Fil: Azevedo, Lucas G.. Instituto Oswaldo Cruz; BrasilFil: Sosa, Ezequiel. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; ArgentinaFil: de Queiroz, Artur T. L.. Instituto Oswaldo Cruz; BrasilFil: Barral, Aldina. Ministerio de Salud de Brasil; BrasilFil: Wheeler, Richard J.. University of Oxford; Reino UnidoFil: Nicolás, Marisa F.. Laboratorio Nacional de Computacao Cientifica; BrasilFil: Farias, Leonardo P.. Instituto Oswaldo Cruz; BrasilFil: Fernández Do Porto, Darío Augusto. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Calculo. - Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Calculo; ArgentinaFil: Ramos, Pablo Ivan P.. Instituto Oswaldo Cruz; BrasilElsevier2024-08info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/258746Azevedo, Lucas G.; Sosa, Ezequiel; de Queiroz, Artur T. L.; Barral, Aldina; Wheeler, Richard J.; et al.; High-throughput prioritization of target proteins for development of new antileishmanial compounds; Elsevier; International Journal for Parasitology: Drugs and Drug Resistance; 25; 8-2024; 1-132211-3207CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://linkinghub.elsevier.com/retrieve/pii/S2211320724000198info:eu-repo/semantics/altIdentifier/doi/10.1016/j.ijpddr.2024.100538info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-nd/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:50:01Zoai:ri.conicet.gov.ar:11336/258746instacron: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 09:50:02.192CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv High-throughput prioritization of target proteins for development of new antileishmanial compounds
title High-throughput prioritization of target proteins for development of new antileishmanial compounds
spellingShingle High-throughput prioritization of target proteins for development of new antileishmanial compounds
Azevedo, Lucas G.
leishmania
drug targets
drug discovery
title_short High-throughput prioritization of target proteins for development of new antileishmanial compounds
title_full High-throughput prioritization of target proteins for development of new antileishmanial compounds
title_fullStr High-throughput prioritization of target proteins for development of new antileishmanial compounds
title_full_unstemmed High-throughput prioritization of target proteins for development of new antileishmanial compounds
title_sort High-throughput prioritization of target proteins for development of new antileishmanial compounds
dc.creator.none.fl_str_mv Azevedo, Lucas G.
Sosa, Ezequiel
de Queiroz, Artur T. L.
Barral, Aldina
Wheeler, Richard J.
Nicolás, Marisa F.
Farias, Leonardo P.
Fernández Do Porto, Darío Augusto
Ramos, Pablo Ivan P.
author Azevedo, Lucas G.
author_facet Azevedo, Lucas G.
Sosa, Ezequiel
de Queiroz, Artur T. L.
Barral, Aldina
Wheeler, Richard J.
Nicolás, Marisa F.
Farias, Leonardo P.
Fernández Do Porto, Darío Augusto
Ramos, Pablo Ivan P.
author_role author
author2 Sosa, Ezequiel
de Queiroz, Artur T. L.
Barral, Aldina
Wheeler, Richard J.
Nicolás, Marisa F.
Farias, Leonardo P.
Fernández Do Porto, Darío Augusto
Ramos, Pablo Ivan P.
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv leishmania
drug targets
drug discovery
topic leishmania
drug targets
drug discovery
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Leishmaniasis, a vector-borne disease, is caused by the infection of Leishmania spp., obligate intracellular protozoan parasites. Presently, human vaccines are unavailable, and the primary treatment relies heavily on systemic drugs, often presenting with suboptimal formulations and substantial toxicity, making new drugs a high priority for LMIC countries burdened by the disease, but a low priority in the agenda of most pharmaceutical companies due to unattractive profit margins. New ways to accelerate the discovery of new, or the repositioning of existing drugs, are needed. To address this challenge, our study aimed to identify potential protein targets shared among clinically-relevant Leishmania species. We employed a subtractive proteomics and comparative genomics approach, integrating high-throughput multi-omics data to classify these targets based on different druggability metrics. This effort resulted in the ranking of 6502 ortholog groups of protein targets across 14 pathogenic Leishmania species. Among the top 20 highly ranked groups, metabolic processes known to be attractive drug targets, including the ubiquitination pathway, aminoacyl-tRNA synthetases, and purine synthesis, were rediscovered. Additionally, we unveiled novel promising targets such as the nicotinate phosphoribosyltransferase enzyme and dihydrolipoamide succinyltransferases. These groups exhibited appealing druggability features, including less than 40% sequence identity to the human host proteome, predicted essentiality, structural classification as highly druggable or druggable, and expression levels above the 50th percentile in the amastigote form. The resources presented in this work also represent a comprehensive collection of integrated data regarding trypanosomatid biology.
Fil: Azevedo, Lucas G.. Instituto Oswaldo Cruz; Brasil
Fil: Sosa, Ezequiel. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina
Fil: de Queiroz, Artur T. L.. Instituto Oswaldo Cruz; Brasil
Fil: Barral, Aldina. Ministerio de Salud de Brasil; Brasil
Fil: Wheeler, Richard J.. University of Oxford; Reino Unido
Fil: Nicolás, Marisa F.. Laboratorio Nacional de Computacao Cientifica; Brasil
Fil: Farias, Leonardo P.. Instituto Oswaldo Cruz; Brasil
Fil: Fernández Do Porto, Darío Augusto. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Calculo. - Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Calculo; Argentina
Fil: Ramos, Pablo Ivan P.. Instituto Oswaldo Cruz; Brasil
description Leishmaniasis, a vector-borne disease, is caused by the infection of Leishmania spp., obligate intracellular protozoan parasites. Presently, human vaccines are unavailable, and the primary treatment relies heavily on systemic drugs, often presenting with suboptimal formulations and substantial toxicity, making new drugs a high priority for LMIC countries burdened by the disease, but a low priority in the agenda of most pharmaceutical companies due to unattractive profit margins. New ways to accelerate the discovery of new, or the repositioning of existing drugs, are needed. To address this challenge, our study aimed to identify potential protein targets shared among clinically-relevant Leishmania species. We employed a subtractive proteomics and comparative genomics approach, integrating high-throughput multi-omics data to classify these targets based on different druggability metrics. This effort resulted in the ranking of 6502 ortholog groups of protein targets across 14 pathogenic Leishmania species. Among the top 20 highly ranked groups, metabolic processes known to be attractive drug targets, including the ubiquitination pathway, aminoacyl-tRNA synthetases, and purine synthesis, were rediscovered. Additionally, we unveiled novel promising targets such as the nicotinate phosphoribosyltransferase enzyme and dihydrolipoamide succinyltransferases. These groups exhibited appealing druggability features, including less than 40% sequence identity to the human host proteome, predicted essentiality, structural classification as highly druggable or druggable, and expression levels above the 50th percentile in the amastigote form. The resources presented in this work also represent a comprehensive collection of integrated data regarding trypanosomatid biology.
publishDate 2024
dc.date.none.fl_str_mv 2024-08
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/11336/258746
Azevedo, Lucas G.; Sosa, Ezequiel; de Queiroz, Artur T. L.; Barral, Aldina; Wheeler, Richard J.; et al.; High-throughput prioritization of target proteins for development of new antileishmanial compounds; Elsevier; International Journal for Parasitology: Drugs and Drug Resistance; 25; 8-2024; 1-13
2211-3207
CONICET Digital
CONICET
url http://hdl.handle.net/11336/258746
identifier_str_mv Azevedo, Lucas G.; Sosa, Ezequiel; de Queiroz, Artur T. L.; Barral, Aldina; Wheeler, Richard J.; et al.; High-throughput prioritization of target proteins for development of new antileishmanial compounds; Elsevier; International Journal for Parasitology: Drugs and Drug Resistance; 25; 8-2024; 1-13
2211-3207
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://linkinghub.elsevier.com/retrieve/pii/S2211320724000198
info:eu-repo/semantics/altIdentifier/doi/10.1016/j.ijpddr.2024.100538
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
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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score 13.13397

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