Discovery of Non-Phosphorylated Glucose-6 Phosphate Isomerase Inhibitors

• Grant number: 16/19141-1
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Start date: January 16, 2017
• End date: July 15, 2017
• Field of knowledge: Biological Sciences - Biochemistry
• Principal Investigator: Artur Torres Cordeiro
• Grantee: Sabrina Gondim Ribeiro Mota
• Supervisor: Ana Rodriguez
• Host Institution: Centro Nacional de Pesquisa em Energia e Materiais (CNPEM). Ministério da Ciência, Tecnologia e Inovação (Brasil). Campinas , SP, Brazil
• Institution abroad: New York University, United States
• Associated to the scholarship: 14/15590-0 - Discovery of new Leishmania mexicana glucose-6-phosphate isomerase inhibitors., BP.DR

Abstract

Leishmaniasis is a parasitic disease with over a million new cases occurring every year. Besides its severity, leishmaniasis treatment is still challenging because all available drugs have important limitations, highlighting the urgent need to develop new drug candidates. Glucose-6-phosphate isomerase (PGI) is considered a promising molecular target for the development of antiparasitic drugs, as it acts on two essential metabolic pathways in different life stages of parasite, glycolysis and gluconeogenesis. This work aims to identify new non-phosphorylated inhibitors of Leishmania mexicana PGI (LmPGI) with potential for the development of anti-parasitic drugs. For this, a kinetic high throughput screening (HTS) assay with fluorescence read out, was developed by coupling the activity of LmPGI with Leuconostoc mesenteroides G6PDH and Clostridium kluyveri Diaphorase. This assay was used to screen 43K compounds from the TIMTEC and Chembridge commercial libraries. The Z factor of the tested plates, in the HTS assay, ranged between 0.70 and 0.92, which indicates the robustness of the assay. The inhibitors confirmed as true hits against LmPGI were tested against the homologue enzyme from Trypanosoma cruzi (TcPGI). The next step of this project is to determine the in vitro efficacy of the inhibitors identified against Leishmania and T. cruzi cells in culture.

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

MERCALDI, GUSTAVO F.; EUFRASIO, AMANDA G.; RANZANI, AMERICO T.; FARIA, JESSICA DO NASCIMENTO; MOTA, SABRINA G. R.; FAGUNDES, MICHELLE; BRUDER, MARJORIE; CORDEIRO, ARTUR T.. Trypanosoma cruzi Malic Enzyme Is the Target for Sulfonamide Hits from the GSK Chagas Box. ACS INFECTIOUS DISEASES, v. 7, n. 8, p. 2455-2471, AUG 13 2021. (15/03336-5, 13/03983-5, 14/15590-0, 18/22202-8, 16/19141-1, 12/23682-7)

MOTA, SABRINA G. R.; MERCALDI, GUSTAVO F.; PEREIRA, JOSE G. C.; OLIVEIRA, PAULO S. L.; RODRIGUEZ, ANA; CORDEIRO, ARTUR T.. First Nonphosphorylated Inhibitors of Phosphoglucose Isomerase Identified by Chemical Library Screening. SLAS DISCOVERY, v. 23, n. 10, p. 1051-1059, DEC 2018. (14/15590-0, 16/14271-4, 16/19141-1, 16/03151-8)