Overview of the Development of DprE1 Inhibitors for Combating the Menace of Tuberculosis

Abstract

Decaprenylphosphoryl-β-d-ribose 2'-epimerase (DprE1), a vital enzyme for cell wall synthesis, plays a crucial role in the formation of lipoarabinomannan and arabinogalactan. It was first reported as a druggable target on the basis of inhibitors discovered in high throughput screening of a drug library. Since then, inhibitors with different types of chemical scaffolds have been reported for their activity against this enzyme. Formation of a covalent or noncovalent bond by the interacting ligand with the enzyme causes loss of its catalytic activity which ultimately leads to the death of the mycobacterium. This Perspective describes various DprE1 inhibitors as anti-TB agents reported to date.

Promiscuous Targets for Antitubercular Drug Discovery: The Paradigm of DprE1 and MmpL3

“…To date, more than 15 chemical classes of compounds inhibiting DprE1 have been reported. These classes encompass both covalent and noncovalent inhibitors, and although the covalent ones are the most successful, several noncovalent inhibitors with significant antitubercular activity have actually been described [45,46].…”

“…Currently, at least 11 different scaffolds have been reported as effective DprE1 inhibitors, either covalent and noncovalent, showing different efficacy in vitro, ex vivo and in vivo [46]. It is noteworthy that the majority of these compounds have been identified through phenotypic screening, then subjected to optimization processes.…”

Virtual screening and free energy estimation for identifying Mycobacterium tuberculosis flavoenzyme DprE1 inhibitors

“…In MTB, the cell wall consists of the polymers of mycolyl-arabinogalactanpeptidoglycan, covalently connected with peptidoglycan and trehalose dimycolate that protects from stress, antibiotics and the hots immune systems [7]. The flavoenzyme decaprenylphosphoryl-β-d-ribose as a cofactor [8][9][10]. Thus, the catalytic activity of DprE1 is one of the potential drug targets in the development of tuberculosis therapy [2,4,7].…”

“…To improve the pharmacological properties of the compounds, chemical scaffold piperazine was added to BTZ. Further, the lead optimization of PBTZ derivatives results in the discovery of more potent compounds which are currently in clinical trials [5,8,11]. In this view, several structurally distinct chemical scaffolds are in drug screening as DprE1 inhibitors.…”

“…In this view, several structurally distinct chemical scaffolds are in drug screening as DprE1 inhibitors. Broadly, these inhibitors can be categorized as covalent or noncovalent, distinctly involved in interaction at the catalytic domain of DprE1 [8,11].…”