Search for potent and selective inhibitors to Mycobacterium tuberculosis dihydroorotate dehydrogenase (MtDHODH)

• Grant number: 20/16316-0
• Support Opportunities: Scholarships in Brazil - Master
• Start date: December 01, 2021
• End date: January 31, 2023
• Field of knowledge: Biological Sciences - Biophysics - Molecular Biophysics
• Principal Investigator: Maria Cristina Nonato
• Grantee: Olívia Teixeira
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Tuberculosis is among the ten diseases that kill the most in the world. Although treatable, resistant strains of Mycobacterium tuberculosis are becoming a serious threat to public health. In 2019 alone, for example, half a million cases of TB resistant to rifampicin (RR-TB), a drug used in combination with isoniazid, pyrazinamide and ethambutol to treat TB, were reported. Of these, 78% are multidrug-resistant (MDR-TB), considered multidrug-resistant because they are resistant to both rifampicin and isoniazid. The enzyme dihydroorotate dehydrogenase (DHODH) present in Mycobacterium tuberculosis fits into this scenario as a promising new drug target against bacteria. DHODH participates in the fourth step of the de novo pyrimidine biosynthesis pathway, responsible for the synthesis of UMP, the precursor of all pyrimidine bases (cytosine, thymine and uracil) and essential for the synthesis of DNA and RNA. DHODHs have been considered a promising target in the development of drugs with anti-inflammatory, immunosuppressive, antiproliferative, antiparasitic, antiviral and bactericidal activity. In this Project, we propose the kinetic and biophysical characterization of the enzyme MtDHODH (using DSF and thermophoresis techniques). We intend to develop a protocol for scanning ligands, and the evaluation and characterization of the inhibitory and selective potential of libraries of DHODH inhibitors, through the combination of inhibitory and binding assays and the determination of the structure of protein-ligand complexes through the use of X-ray diffraction techniques. In this project we plan to initiate the evaluation of the DHODH enzyme of Mycobacterium Tuberculosis (MtDHODH) as a target for the development of drugs against tuberculosis, as as crucial step in the target-based drug discovery pipeline. (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)

TEIXEIRA, OLIVIA; MARTINS, INGRID BERNARDES SANTANA; FROES, THAMIRES QUADROS; DE ARAUJO, ALEXANDRE SUMAN; NONATO, MARIA CRISTINA. Kinetic and structural studies of Mycobacterium tuberculosis dihydroorotate dehydrogenase reveal new insights into class 2 DHODH inhibition. BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS, v. 1867, n. 7, p. 10-pg., 2023-07-01. (19/25532-1, 20/16316-0)