An experimental target-based platform in yeast for screening Plasmodium vivax deoxyhypusine synthase inhibitors

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Autor(es): dc.contributorUniversity of Gothenburg-
Autor(es): dc.contributorUniversidade Estadual Paulista (UNESP)-
Autor(es): dc.contributorUniversidade Estadual de Campinas (UNICAMP)-
Autor(es): dc.creatorSilva, Suélen Fernandes-
Autor(es): dc.creatorKlippel, Angélica Hollunder-
Autor(es): dc.creatorSigurdardóttir, Sunniva-
Autor(es): dc.creatorMahdizadeh, Sayyed Jalil-
Autor(es): dc.creatorTiukova, Ievgeniia-
Autor(es): dc.creatorBourgard, Catarina-
Autor(es): dc.creatorSalazar-Alvarez, Luis Carlos-
Autor(es): dc.creatorDo Amaral Prado, Heloísa Monteiro-
Autor(es): dc.creatorde Araujo, Renan Vinicius-
Autor(es): dc.creatorCosta, Fabio Trindade Maranhão-
Autor(es): dc.creatorBilsland, Elizabeth-
Autor(es): dc.creatorKing, Ross D.-
Autor(es): dc.creatorMassirer, Katlin Brauer-
Autor(es): dc.creatorEriksson, Leif A.-
Autor(es): dc.creatorBengtson, Mário Henrique-
Autor(es): dc.creatorZanelli, Cleslei Fernando-
Autor(es): dc.creatorSunnerhagen, Per-
Data de aceite: dc.date.accessioned2025-08-21T19:29:04Z-
Data de disponibilização: dc.date.available2025-08-21T19:29:04Z-
Data de envio: dc.date.issued2025-04-29-
Data de envio: dc.date.issued2024-11-30-
Fonte completa do material: dc.identifierhttp://dx.doi.org/10.1371/journal.pntd.0012690-
Fonte completa do material: dc.identifierhttps://hdl.handle.net/11449/299283-
Fonte: dc.identifier.urihttp://educapes.capes.gov.br/handle/11449/299283-
Descrição: dc.descriptionThe enzyme deoxyhypusine synthase (DHS) catalyzes the first step in the post-translational modification of the eukaryotic translation factor 5A (eIF5A). This is the only protein known to contain the amino acid hypusine, which results from this modification. Both eIF5A and DHS are essential for cell viability in eukaryotes, and inhibiting DHS is a promising strategy to develop new therapeutic alternatives. DHS proteins from many are sufficiently different from their human orthologs for selective targeting against infectious diseases; however, no DHS inhibitor selective for parasite orthologs has previously been reported. Here, we established a yeast surrogate genetics platform to identify inhibitors of DHS from Plasmodium vivax, one of the major causative agents of malaria. We constructed genetically modified Saccharomyces cerevisiae strains expressing DHS genes from Homo sapiens (HsDHS) or P. vivax (PvDHS) in place of the endogenous DHS gene from S. cerevisiae. Compared with a HsDHS complemented strain with a different genetic background that we previously generated, this new strain background was ~60-fold more sensitive to an inhibitor of human DHS. Initially, a virtual screen using the ChEMBL-NTD database was performed. Candidate ligands were tested in growth assays using the newly generated yeast strains expressing heterologous DHS genes. Among these, two showed promise by preferentially reducing the growth of the PvDHS-expressing strain. Further, in a robotized assay, we screened 400 compounds from the Pathogen Box library using the same S. cerevisiae strains, and one compound preferentially reduced the growth of the PvDHS-expressing yeast strain. Western blot revealed that these compounds significantly reduced eIF5A hypusination in yeast. The compounds showed antiplasmodial activity in the asexual erythrocyte stage; EC50 in high nM to low μM range, and low cytotoxicity. Our study demonstrates that this yeast-based platform is suitable for identifying and verifying candidate small molecule DHS inhibitors, selective for the parasite over the human ortholog.-
Descrição: dc.descriptionConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)-
Descrição: dc.descriptionVetenskapsrådet-
Descrição: dc.descriptionFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)-
Descrição: dc.descriptionCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)-
Descrição: dc.descriptionDepartment of Chemistry and Molecular Biology University of Gothenburg-
Descrição: dc.descriptionChemistry Institute São Paulo State University-UNESP, São Paulo-
Descrição: dc.descriptionCenter for Medicinal Chemistry-CQMED Center for Molecular Biology and Genetic Engineering-CBMEG Universidade Estadual de Campinas, São Paulo-
Descrição: dc.descriptionSchool of Pharmaceutical Sciences São Paulo State University—UNESP, São Paulo-
Descrição: dc.descriptionDepartment of Life Sciences, Chalmers-
Descrição: dc.descriptionLaboratory of Tropical Diseases Institute of Biology Universidade Estadual de Campinas-UNICAMP, São Paulo-
Descrição: dc.descriptionDepartment of Structural and Functional Biology Institute of Biology Universidade Estadual de Campinas-UNICAMP, São Paulo-
Descrição: dc.descriptionDepartment of Biochemistry and Tissue Biology Institute of Biology Universidade Estadual de Campinas, São Paulo-
Descrição: dc.descriptionChemistry Institute São Paulo State University-UNESP, São Paulo-
Descrição: dc.descriptionSchool of Pharmaceutical Sciences São Paulo State University—UNESP, São Paulo-
Descrição: dc.descriptionCNPq: 141241/2019-5-
Descrição: dc.descriptionVetenskapsrådet: 2016-05627-
Descrição: dc.descriptionFAPESP: 2018/16672-1-
Descrição: dc.descriptionVetenskapsrådet: 2019-0368-
Descrição: dc.descriptionFAPESP: 2019/24812-0-
Descrição: dc.descriptionVetenskapsrådet: 2021-03667-
Descrição: dc.descriptionCNPq: 380882/2023-0-
Descrição: dc.descriptionCNPq: 380893/2023-1-
Descrição: dc.descriptionCAPES: 8887.161266/2017-00-
Descrição: dc.descriptionFAPESP: 88887.304810/2018-00-
Idioma: dc.languageen-
Relação: dc.relationPLoS Neglected Tropical Diseases-
???dc.source???: dc.sourceScopus-
Título: dc.titleAn experimental target-based platform in yeast for screening Plasmodium vivax deoxyhypusine synthase inhibitors-
Tipo de arquivo: dc.typelivro digital-
Aparece nas coleções:Repositório Institucional - Unesp

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