Frist nonphosphorylated inhibitors of phosphoglucose isomerase identified by chemical library screening

Author(s)

Sabrina Gondim Ribeiro Mota

• Document type: Doctoral Thesis
• Press: Campinas, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Instituto de Biologia
• Defense date: 2018-07-10

Examining board members

Artur Torres Cordeiro; Andre Luís Berteli Ambrosio; Juliana Helena Costa Smetana; Marcos Vicente de Albuquerque Salles Navarro; Rafael Elias Marques

• Advisor: Artur Torres Cordeiro

Abstract

Chagas disease and leishmaniasis are human infections caused by protozoan parasites of the genus Trypanosoma and Leishmania, respectively. Besides their severity and global impact, their treatments are still challenging. Currently, available drugs share important limitations, regarding mainly to efficacy and safety, highlighting the urgent need to develop new drugs candidates. Glucose-6-phosphate isomerase (PGI), also known as phosphoglucose isomerase, is considered a promising target for the development of anti-parasitic drugs, as it acts on two essential metabolic pathways, glycolysis and gluconeogenesis, which are important for different parasite life cycle stage. This work aims to identify new inhibitors of Leishmania mexicana PGI (LmPGI) with potential for the development of anti-parasitic drugs. A fluorescence based high throughput screening 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 LLC commercial libraries. After confirmatory assays, selected LmPGI inhibitors were tested against the homologous PGIs of Trypanosoma cruzi (TcPGI) and human (HsPGI). The PGI hits reported herein are effective against trypanosomatid PGIs, with IC50 values in the low micromolar range, but also against the human homologous enzyme. A computational analysis of cavities present on LmPGI crystallographic structure suggests a potential binding site for the inhibitors that demonstrated 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