Discovery of new Leishmania mexicana glucose-6-phosphate isomerase inhibitors.

• Grant number: 14/15590-0
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: September 01, 2014
• End date: March 01, 2018
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Artur Torres Cordeiro
• Grantee: Sabrina Gondim Ribeiro Mota
• Host Institution: Centro Nacional de Pesquisa em Energia e Materiais (CNPEM). Ministério da Ciência, Tecnologia e Inovação (Brasil). Campinas , SP, Brazil
• Associated scholarship(s): 16/19141-1 - Discovery of Non-Phosphorylated Glucose-6 Phosphate Isomerase Inhibitors, BE.EP.DR

Abstract

Leishmaniasis is a parasitic disease associated with infection by flagellate protozoa of the genus Leishmania ssp. Currently all available options for the treatment of this disease have limited use due to the development of parasite resistance, difficulties in administration, long period of treatment, toxicity or high cost. Glucose-6-phosphate isomerase (PGI) is considered as a promising molecular target for the development of antiparasitic drugs as it acts on essential metabolic pathways in different cycle stages of parasite life. PGI catalyzes the reversible isomerization of glucose-6-phosphate (G6P) to fructose-6-phosphate (F6P) and thus participates in both the glycolytic and gluconeogenesis. This project aim to identify new unphosphorylated inhibitors of Leishmania mexicana PGI (LmPGI), and, if possible, selective against the parasite enzyme; ie. no activity or reduced activity against human PGI (HsPGI). For this a HTS assay (abbreviation for High Throughput Screening) will be developed to screen libraries of diversity chemical compounds (10,000 compounds) and a natural derivative library (3040 compounds) commercially purchased and available at the TIMTEC Laboratory bioassays LNBio / CNPEM. After the primary HTS, the inhibitors identified will be tested against LmPGI and HsPGI to assess the parasite enzyme selectivity. Then the compounds are grouped by similarity and structural representatives. From each novel class of inhibitors X-ray crystallography will be used to determine the mechanism of inhibition and binding site. The most potent inhibitors will be used to assess the leishmanicidal effect against parasites cultures. The results of this project may lead to discovery of new drug candidates against leishmaniasis.

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)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

MOTA, Sabrina Gondim Ribeiro. Frist nonphosphorylated inhibitors of phosphoglucose isomerase identified by chemical library screening. 2018. Doctoral Thesis - Universidade Estadual de Campinas (UNICAMP). Instituto de Biologia Campinas, SP.