New hit compounds against Trypanosoma cruzi derived from mining yeast chemogenomic profiling data

Autores
Didier Garnham, Mercedes Monica; Urán Landaburu, Héctor Lionel; Salas Sarduy, Emir; Agüero, Fernan Gonzalo
Año de publicación
2026
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Chagas disease, caused by Trypanosoma cruzi, remains a major neglected tropical disease with limited therapeutic options. To accelerate drug discovery, we developed a bioinformatic and chemoinformatic pipeline that integrates chemogenomic profiling data from Saccharomyces cerevisiae with orthology and essentiality information from trypanosomatids. First, we integrated data from 5 reference yeast chemogenomic screens which assayed a total of 2,788 compounds against a collection of 5,811 gene-deletion strains thus providing a rich matrix of ~ 270,000 gene-drug associations. Using these data as input the pipeline filtered and prioritized 193 candidate bioactive compounds with links to conserved parasite orthologs. Following manual curation, 22 compounds were selected for experimental evaluation. In vitro assays against intracellular T. cruzi revealed three novel hits with micromolar EC_50 values and favorable selectivity indices. This work demonstrates that comparative chemogenomics can be leveraged for drug repositioning in parasitic protozoa, providing a tractable strategy to enrich lead-like compounds and expand the chemical space available for Chagas disease drug discovery. Importantly, both the curated yeast chemogenomic dataset and the analysis pipeline are reusable resources, and the prioritized compound list offers a ready-to-test chemical space that can be further explored, validated, and expanded by other researchers and for additional organisms.
Fil: Didier Garnham, Mercedes Monica. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas. - Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Biotecnológicas; Argentina
Fil: Urán Landaburu, Héctor Lionel. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas. - Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Biotecnológicas; Argentina
Fil: Salas Sarduy, Emir. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas. - Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Biotecnológicas; Argentina
Fil: Agüero, Fernan Gonzalo. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas. - Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Biotecnológicas; Argentina
Materia
CHEMICAL GENOMICS
DRUG DISCOVERY
DRUG REPOSITIONING
TRYPANOSOMA CRUZI
CHAGAS DISEASE
YEAST DELETION STRAINS
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/285172
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/285172
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling New hit compounds against Trypanosoma cruzi derived from mining yeast chemogenomic profiling dataDidier Garnham, Mercedes MonicaUrán Landaburu, Héctor LionelSalas Sarduy, EmirAgüero, Fernan GonzaloCHEMICAL GENOMICSDRUG DISCOVERYDRUG REPOSITIONINGTRYPANOSOMA CRUZICHAGAS DISEASEYEAST DELETION STRAINShttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Chagas disease, caused by Trypanosoma cruzi, remains a major neglected tropical disease with limited therapeutic options. To accelerate drug discovery, we developed a bioinformatic and chemoinformatic pipeline that integrates chemogenomic profiling data from Saccharomyces cerevisiae with orthology and essentiality information from trypanosomatids. First, we integrated data from 5 reference yeast chemogenomic screens which assayed a total of 2,788 compounds against a collection of 5,811 gene-deletion strains thus providing a rich matrix of ~ 270,000 gene-drug associations. Using these data as input the pipeline filtered and prioritized 193 candidate bioactive compounds with links to conserved parasite orthologs. Following manual curation, 22 compounds were selected for experimental evaluation. In vitro assays against intracellular T. cruzi revealed three novel hits with micromolar EC_50 values and favorable selectivity indices. This work demonstrates that comparative chemogenomics can be leveraged for drug repositioning in parasitic protozoa, providing a tractable strategy to enrich lead-like compounds and expand the chemical space available for Chagas disease drug discovery. Importantly, both the curated yeast chemogenomic dataset and the analysis pipeline are reusable resources, and the prioritized compound list offers a ready-to-test chemical space that can be further explored, validated, and expanded by other researchers and for additional organisms.Fil: Didier Garnham, Mercedes Monica. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas. - Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Biotecnológicas; ArgentinaFil: Urán Landaburu, Héctor Lionel. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas. - Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Biotecnológicas; ArgentinaFil: Salas Sarduy, Emir. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas. - Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Biotecnológicas; ArgentinaFil: Agüero, Fernan Gonzalo. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas. - Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Biotecnológicas; ArgentinaAmerican Society for Microbiology2026-01info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/285172Didier Garnham, Mercedes Monica; Urán Landaburu, Héctor Lionel; Salas Sarduy, Emir; Agüero, Fernan Gonzalo; New hit compounds against Trypanosoma cruzi derived from mining yeast chemogenomic profiling data; American Society for Microbiology; Antimicrobial Agents and Chemotherapy; 1-2026; 1-252573-2293CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.26434/chemrxiv.10001505/v2info:eu-repo/semantics/altIdentifier/url/https://chemrxiv.org/doi/full/10.26434/chemrxiv.10001505/v2info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2026-08-25T14:32:24Zoai:ri.conicet.gov.ar:11336/285172instacron: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:34982026-08-25 14:32:24.588CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv New hit compounds against Trypanosoma cruzi derived from mining yeast chemogenomic profiling data
title New hit compounds against Trypanosoma cruzi derived from mining yeast chemogenomic profiling data
spellingShingle New hit compounds against Trypanosoma cruzi derived from mining yeast chemogenomic profiling data
Didier Garnham, Mercedes Monica
CHEMICAL GENOMICS
DRUG DISCOVERY
DRUG REPOSITIONING
TRYPANOSOMA CRUZI
CHAGAS DISEASE
YEAST DELETION STRAINS
title_short New hit compounds against Trypanosoma cruzi derived from mining yeast chemogenomic profiling data
title_full New hit compounds against Trypanosoma cruzi derived from mining yeast chemogenomic profiling data
title_fullStr New hit compounds against Trypanosoma cruzi derived from mining yeast chemogenomic profiling data
title_full_unstemmed New hit compounds against Trypanosoma cruzi derived from mining yeast chemogenomic profiling data
title_sort New hit compounds against Trypanosoma cruzi derived from mining yeast chemogenomic profiling data
dc.creator.none.fl_str_mv Didier Garnham, Mercedes Monica
Urán Landaburu, Héctor Lionel
Salas Sarduy, Emir
Agüero, Fernan Gonzalo
author Didier Garnham, Mercedes Monica
author_facet Didier Garnham, Mercedes Monica
Urán Landaburu, Héctor Lionel
Salas Sarduy, Emir
Agüero, Fernan Gonzalo
author_role author
author2 Urán Landaburu, Héctor Lionel
Salas Sarduy, Emir
Agüero, Fernan Gonzalo
author2_role author
author
author
dc.subject.none.fl_str_mv CHEMICAL GENOMICS
DRUG DISCOVERY
DRUG REPOSITIONING
TRYPANOSOMA CRUZI
CHAGAS DISEASE
YEAST DELETION STRAINS
topic CHEMICAL GENOMICS
DRUG DISCOVERY
DRUG REPOSITIONING
TRYPANOSOMA CRUZI
CHAGAS DISEASE
YEAST DELETION STRAINS
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Chagas disease, caused by Trypanosoma cruzi, remains a major neglected tropical disease with limited therapeutic options. To accelerate drug discovery, we developed a bioinformatic and chemoinformatic pipeline that integrates chemogenomic profiling data from Saccharomyces cerevisiae with orthology and essentiality information from trypanosomatids. First, we integrated data from 5 reference yeast chemogenomic screens which assayed a total of 2,788 compounds against a collection of 5,811 gene-deletion strains thus providing a rich matrix of ~ 270,000 gene-drug associations. Using these data as input the pipeline filtered and prioritized 193 candidate bioactive compounds with links to conserved parasite orthologs. Following manual curation, 22 compounds were selected for experimental evaluation. In vitro assays against intracellular T. cruzi revealed three novel hits with micromolar EC_50 values and favorable selectivity indices. This work demonstrates that comparative chemogenomics can be leveraged for drug repositioning in parasitic protozoa, providing a tractable strategy to enrich lead-like compounds and expand the chemical space available for Chagas disease drug discovery. Importantly, both the curated yeast chemogenomic dataset and the analysis pipeline are reusable resources, and the prioritized compound list offers a ready-to-test chemical space that can be further explored, validated, and expanded by other researchers and for additional organisms.
Fil: Didier Garnham, Mercedes Monica. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas. - Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Biotecnológicas; Argentina
Fil: Urán Landaburu, Héctor Lionel. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas. - Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Biotecnológicas; Argentina
Fil: Salas Sarduy, Emir. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas. - Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Biotecnológicas; Argentina
Fil: Agüero, Fernan Gonzalo. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas. - Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Biotecnológicas; Argentina
description Chagas disease, caused by Trypanosoma cruzi, remains a major neglected tropical disease with limited therapeutic options. To accelerate drug discovery, we developed a bioinformatic and chemoinformatic pipeline that integrates chemogenomic profiling data from Saccharomyces cerevisiae with orthology and essentiality information from trypanosomatids. First, we integrated data from 5 reference yeast chemogenomic screens which assayed a total of 2,788 compounds against a collection of 5,811 gene-deletion strains thus providing a rich matrix of ~ 270,000 gene-drug associations. Using these data as input the pipeline filtered and prioritized 193 candidate bioactive compounds with links to conserved parasite orthologs. Following manual curation, 22 compounds were selected for experimental evaluation. In vitro assays against intracellular T. cruzi revealed three novel hits with micromolar EC_50 values and favorable selectivity indices. This work demonstrates that comparative chemogenomics can be leveraged for drug repositioning in parasitic protozoa, providing a tractable strategy to enrich lead-like compounds and expand the chemical space available for Chagas disease drug discovery. Importantly, both the curated yeast chemogenomic dataset and the analysis pipeline are reusable resources, and the prioritized compound list offers a ready-to-test chemical space that can be further explored, validated, and expanded by other researchers and for additional organisms.
publishDate 2026
dc.date.none.fl_str_mv 2026-01
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/11336/285172
Didier Garnham, Mercedes Monica; Urán Landaburu, Héctor Lionel; Salas Sarduy, Emir; Agüero, Fernan Gonzalo; New hit compounds against Trypanosoma cruzi derived from mining yeast chemogenomic profiling data; American Society for Microbiology; Antimicrobial Agents and Chemotherapy; 1-2026; 1-25
2573-2293
CONICET Digital
CONICET
url http://hdl.handle.net/11336/285172
identifier_str_mv Didier Garnham, Mercedes Monica; Urán Landaburu, Héctor Lionel; Salas Sarduy, Emir; Agüero, Fernan Gonzalo; New hit compounds against Trypanosoma cruzi derived from mining yeast chemogenomic profiling data; American Society for Microbiology; Antimicrobial Agents and Chemotherapy; 1-2026; 1-25
2573-2293
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.26434/chemrxiv.10001505/v2
info:eu-repo/semantics/altIdentifier/url/https://chemrxiv.org/doi/full/10.26434/chemrxiv.10001505/v2
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv American Society for Microbiology
publisher.none.fl_str_mv American Society for Microbiology
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 13.24418

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