First Nonphosphorylated Inhibitors of Phosphoglucose Isomerase Identified by Chemical Library Screening

Autor(es)

Mota, Sabrina G. R. ^{[1, 2]} ; Mercaldi, Gustavo F. ^[2] ; Pereira, Jose G. C. ^[2] ; Oliveira, Paulo S. L. ^[2] ; Rodriguez, Ana ^[3] ; Cordeiro, Artur T. ^[2]

Afiliação do(s) autor(es)

^[1] Univ Estadual Campinas, Inst Biol, Campinas, SP - Brazil

^[2] Brazilian Ctr Res Energy & Mat, Brazilian Biosci Natl Lab, St Giuseppe Maximo Scolfaro, BR-13083970 Campinas, SP - Brazil

^[3] NYU, Sch Med, Dept Microbiol, New York, NY 10016 - USA

• Tipo de documento: Artigo Científico
• Fonte: SLAS DISCOVERY; v. 23, n. 10, p. 1051-1059, DEC 2018.
• Citações Web of Science: 1

Resumo

Human African trypanosomiasis, Chagas disease, and leishmaniasis are human infections caused by kinetoplastid parasites of the genera Trypanosoma and Leishmania. Besides their severity and global impact, treatments are still challenging. Currently available drugs have important limitations, highlighting the urgent need to develop new drugs. Phosphoglucose isomerase (PGI) is considered a promising target for the development of antiparasitic drugs, as it acts on two essential metabolic pathways, glycolysis and gluconeogenesis. Herein, we describe the identification of new nonphosphorylated inhibitors of Leishmania mexicana PGI (LmPGI), with the potential for the development of antiparasitic drugs. A fluorescence-based high-throughput screening (HTS) assay was developed by coupling the activities of recombinant LmPGI with glucose-6-phosphate dehydrogenase and diaphorase. This coupled assay was used to screen 42,720 compounds from ChemBridge and TimTec commercial libraries. After confirmatory assays, selected LmPGI inhibitors were tested against homologous Trypanosoma cruzi and humans. The PGI hits are effective against trypanosomatid PGIs, with IC50 values in the micromolar range, and also against the human homologous enzyme. A computational analysis of cavities present on PGI's crystallographic structure suggests a potential binding site for the proposed mixed-type inhibition mechanism. (AU)

• Processo FAPESP: 14/15590-0 - Descoberta de novos inibidores da enzima Glicose-6-fosfato isomerase de Leishmania mexicana.
• Beneficiário: Sabrina Gondim Ribeiro Mota
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 16/14271-4 - Aperfeiçoamento dos inibidores da enzima G6PDH para desenvolvimento de fármacos contra Chagas
• Beneficiário: Artur Torres Cordeiro
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 16/19141-1 - Descoberta de inibidores não fosforilados da enzima Glicose-6 fosfato isomerase
• Beneficiário: Sabrina Gondim Ribeiro Mota
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado
• Processo FAPESP: 16/03151-8 - Aminoacil-tRNA Sintetases como Alvos para o Desenvolvimento de Agrobactericidas destinados ao Controle de Doenças de Plantas Causadas por espécies de Xanthomonas
• Beneficiário: Gustavo Fernando Mercaldi
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado