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Current Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Review Article

Multifunctional Enzymes as Targets for the Treatment of Tuberculosis: Paving the Way for New Anti-TB Drugs

Author(s): Carla Sílvia Silva Teixeira, Nuno M.F.S.A. Cerqueira and Sérgio Filipe Sousa*

Volume 28, Issue 28, 2021

Published on: 29 December, 2020

Page: [5847 - 5882] Pages: 36

DOI: 10.2174/0929867328666201229122722

Price: $65

Abstract

In spite of the medical and technological developments of the last centuries, Tuberculosis (TB) has remained a challenging disease, with a limited number of therapeutic options, particularly in light of the increase in drug-resistant cases. The search for new molecules continues, with several candidates currently in clinical testing and ongoing efforts to identify novel targets. This work summarizes recent developments on anti-TB therapy, starting by discussing the current epidemiologic status and presenting an overview of the history of anti-tuberculosis drug discovery. Special attention is dedicated to five multifunctional enzymes that are regarded as promising targets for new anti-TB drugs: 5-aminoimidazole-4-carboxamide ribonucleotide transformylase/IMP cyclohydrolase (ATIC); 3,4-dihydroxy-2-butanone 4-phosphate synthase (DHBPS)/GTP cyclohydrolase II (GCHII); glutamine dependent NAD+ Synthetase (NadE); chorismate synthase (CS); and Tryptophan synthase (TS). These enzymes are involved in metabolic pathways critical for the M. tuberculosis survival, growth or replication, but that are not expressed in humans or have significant differences in terms of functionality, which makes them appealing targets. Their function, structure, possible catalytic mechanisms, and current inhibition strategies and inhibitors are reviewed and discussed.

Keywords: Tuberculosis, drug targets, multifunctional enzymes, purine biosynthesis, co-factor biosynthesis, amino acid biosynthesis.

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