Design and synthesis of Steroid-based irreversible inhibitors of glucose-6-phosphate dehydrogenase: mapping of the binding site

• Grant number: 13/16534-4
• Support Opportunities: Regular Research Grants
• Start date: December 01, 2013
• End date: May 31, 2016
• Field of knowledge: Physical Sciences and Mathematics - Chemistry - Organic Chemistry
• Principal Investigator: Marjorie Christine Paule Bruder
• Grantee: Marjorie Christine Paule Bruder
• Host Institution: Centro Nacional de Pesquisa em Energia e Materiais (CNPEM). Ministério da Ciência, Tecnologia e Inovação (Brasil). Campinas , SP, Brazil
• Associated researchers: Artur Torres Cordeiro ; Ronaldo Aloise Pilli

Abstract

Glucose-6-phosphate dehydrogenase (G6PDH) is an important regulatory enzyme associated with disorders such as obesity, cardiovascular diseases, and cancer. G6PDH is also essential for the survival of the Trypanosoma parasite, the causative agent of Chagas' disease. DHEA (dehydroepiandrosterone), an endogenous steroid, and related molecules have shown to inhibit G6PDH in an uncompetitive manner, but there are no reports of the isolation of a ligand-enzyme complex, neither has the allosteric binding site been identified. Herein, we wish to synthesize a series of about 40 steroid analogues bearing reactive moieties toward nucleophiles, in view of forming a covalent bond with one of the nucleophilic residues of the enzyme G6PDH near the binding site of the steroid core. The objective is to be able to isolate the adducts via crystallization techniques and analyze the structures by means of X-ray crystallographic and/or mass spectrometric analysis in order to explore ligand binding and to identify structural features necessary for inhibition. Such achievement should firstly enable the understanding of the intermolecular interaction of steroids such as DHEA with G6PDH. It should also allow the design and development of new inhibitors of the enzyme and provide additional information for the comprehensive study of G6PDH related disorders. Our proposal involves a multidisciplinary approach that combines expertise in organic synthesis, molecular biology, X-ray crystallography, as well as mass spectrometry to map the steroid specific binding site of G6PDH. (AU)

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)

NACIUK, FABRICIO FREDO; FARIA, JESSICA DO NASCIMENTO; EUFRASIO, AMANDA GONCALVES; CORDEIRO, ARTUR TORRES; BRUDER, MARJORIE. Development of Selective Steroid Inhibitors for the Glucose-6-phosphate Dehydrogenase from Trypanosoma cruzi. ACS Medicinal Chemistry Letters, v. 11, n. 6, p. 1250-1256, JUN 11 2020. (13/16534-4, 16/14271-4, 18/22202-8)