Advanced search
Start date
Betweenand
(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

First Nonphosphorylated Inhibitors of Phosphoglucose Isomerase Identified by Chemical Library Screening

Full text
Author(s):
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]
Total Authors: 6
Affiliation:
[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
Total Affiliations: 3
Document type: Journal article
Source: SLAS DISCOVERY; v. 23, n. 10, p. 1051-1059, DEC 2018.
Web of Science Citations: 1
Abstract

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)

FAPESP's process: 16/19141-1 - Discovery of non-phosphorylated glucose-6 phosphate isomerase inhibitors
Grantee:Sabrina Gondim Ribeiro Mota
Support type: Scholarships abroad - Research Internship - Doctorate
FAPESP's process: 14/15590-0 - Discovery of new Leishmania mexicana glucose-6-phosphate isomerase inhibitors
Grantee:Sabrina Gondim Ribeiro Mota
Support type: Scholarships in Brazil - Doctorate
FAPESP's process: 16/14271-4 - Optimization G6PDH inhibitors towards the development of drugs against Chagas diseases
Grantee:Artur Torres Cordeiro
Support type: Regular Research Grants
FAPESP's process: 16/03151-8 - Aminoacil-tRNA synthetases as targets for development of Agrobactericides intented for control of plant diseases caused by Xanthomonas species
Grantee:Gustavo Fernando Mercaldi
Support type: Scholarships in Brazil - Post-Doctorate