| 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: | 14/15590-0 - Discovery of new Leishmania mexicana glucose-6-phosphate isomerase inhibitors. |
| Grantee: | Sabrina Gondim Ribeiro Mota |
| Support Opportunities: | 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 Opportunities: | Regular Research Grants |
| FAPESP's process: | 16/19141-1 - Discovery of Non-Phosphorylated Glucose-6 Phosphate Isomerase Inhibitors |
| Grantee: | Sabrina Gondim Ribeiro Mota |
| Support Opportunities: | Scholarships abroad - Research Internship - Doctorate |
| 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 Opportunities: | Scholarships in Brazil - Post-Doctoral |