Development of a novel Indoleamine 2,3-Dioxygenase-1 (IDO1) inhibitor for neuropathic pain treatment

• Grant number: 22/09604-5
• Support Opportunities: Scholarships in Brazil - Doctorate
• Effective date (Start): September 01, 2023
• Status: Discontinued
• Field of knowledge: Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
• Principal Investigator: Daniela Barretto Barbosa Trivella
• Grantee: Paulo Jardim
• Host Institution: Centro Nacional de Pesquisa em Energia e Materiais (CNPEM). Ministério da Ciência, Tecnologia e Inovação (Brasil). Campinas , SP, Brazil

Abstract

Neuropathic pain represents one of the most important types of chronic pain, commenting about 10% of the global population. That condition could be triggered by two principal factors: (1) pathology affecting the somatosensorial nervous system and (2) damage caused directly to the central or peripherical nervous system. Known treatments for neuropathic pain are limited and scarce, therefore new pharmacological approaches are required. Preliminary results obtained by Prof. Dr. Thiago Cunha's research group (co-advisor in this project) demonstrated that neuropathic pain could be ablated or reduced by tryptophan catabolic pathway inhibition, particularly the kynurenines pathway (kynpath), indicating this pathway as a potential pharmacological target. The first enzyme in kynpath, indoleamine-2,3-dioxygenase 1 (IDO1), compromised the substrate tryptophan into the pathway and is considered a key enzyme in kynpath. For this reason, IDO1 was elected as a molecular target in this project which is dedicated to the discovery and characterization of new IDO1 inhibitors. We initiate this project at LNBio-CNPEM with in vivo assays to find new inhibitors, then characterize and enhance the molecules, the best hits will be selected for in vivo assays in pre-clinical models of neuropathic pain, already established at FMRP-USP. This project was initiated in 2021 due to the acceptance of the Ph.D. student at PPG-Farmacologia (FMRP-USP), presenting already important results for his evolution. Firstly, the IDO1 expression and purification procedures were implemented and validated to obtain the enzyme in the required quantities and high purity level. IDO1 was produced and characterized with biophysics assays to evaluate secondary structure profile, structural stability, and oligomeric profile. We also made biochemical characterization using colorimetric and fluorescence assays. The high throughput screening (HTS) assay will be performed against the compound libraries using a fluorescence assay. Simultaneously, we are working to implement crystallization and structure characterization of IDO1 and its complexes with inhibitors by X-ray crystallography. (AU)