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dc.contributor.author
Ranzani, Americo T.
dc.contributor.author
Nowicki, Cristina
dc.contributor.author
Wilkinson, Shane R.
dc.contributor.author
Cordeiro, Artur T.
dc.date.available
2018-06-04T19:57:18Z
dc.date.issued
2017-10
dc.identifier.citation
Ranzani, Americo T.; Nowicki, Cristina; Wilkinson, Shane R.; Cordeiro, Artur T.; Identification of Specific Inhibitors of Trypanosoma cruzi Malic Enzyme Isoforms by Target-Based HTS; SAGE Publications; SLAS Discovery; 22; 9; 10-2017; 1150-1161
dc.identifier.issn
2472-5552
dc.identifier.uri
http://hdl.handle.net/11336/47200
dc.description.abstract
Trypanosoma cruzi is the causative agent of Chagas disease. The lack of an efficient and safe treatment supports the research into novel metabolic targets, with the malic enzyme (ME) representing one such potential candidate. T. cruzi expresses a cytosolic (TcMEc) and a mitochondrial (TcMEm) ME isoform, with these activities functioning to generate NADPH, a key source of reducing equivalents that drives a range of anabolic and protective processes. To identify specific inhibitors that target TcMEs, two independent high-throughput screening strategies using a diversity library containing 30,000 compounds were employed. IC50 values of 262 molecules were determined for both TcMEs, as well as for three human ME isoforms, with the inhibitors clustered into six groups according to their chemical similarity. The most potent hits belonged to a sulfonamide group that specifically target TcMEc. Moreover, several selected inhibitors of both TcMEs showed a trypanocidal effect against the replicative forms of T. cruzi. The chemical diversity observed among those compounds that inhibit TcMEs activity emphasizes the druggability of these enzymes, with a sulfonamide-based subset of compounds readily able to block TcMEc function at a low nanomolar range.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
SAGE Publications
dc.rights
info:eu-repo/semantics/openAccess
dc.rights.uri
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.subject
Chagas Disease
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Hts
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Malic Enzyme
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Sulfonamides
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Trypanosoma Cruzi
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Otras Ciencias Biológicas
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Ciencias Biológicas
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CIENCIAS NATURALES Y EXACTAS
dc.title
Identification of Specific Inhibitors of Trypanosoma cruzi Malic Enzyme Isoforms by Target-Based HTS
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2018-06-04T17:26:37Z
dc.journal.volume
22
dc.journal.number
9
dc.journal.pagination
1150-1161
dc.journal.pais
Estados Unidos
dc.description.fil
Fil: Ranzani, Americo T.. Brazilian Center for Research in Energy and Material; Brasil. Universidade Estadual de Campinas; Brasil
dc.description.fil
Fil: Nowicki, Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; Argentina
dc.description.fil
Fil: Wilkinson, Shane R.. Queen Mary University of London; Reino Unido
dc.description.fil
Fil: Cordeiro, Artur T.. Brazilian Center for Research in Energy and Material; Brasil
dc.journal.title
SLAS Discovery
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1177/2472555217706649
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/http://journals.sagepub.com/doi/10.1177/2472555217706649
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