Decaprenyl-phosphoryl-ribose 2′-epimerase (DprE1): challenging target for antitubercular drug discovery

Abstract

Tuberculosis has proved harmful to the entire history of mankind from past several decades. Decaprenyl-phosphoryl-ribose 2′-epimerase (DprE1) is a recent target which was identified in 2009 but unfortunately it is neither explored nor crossed phase II. In past several decades few targets were identified for effective antitubercular drug discovery. Resistance is the major problem for effective antitubercular drug discovery. Arabinose is constituent of mycobacterium cell wall. Biosynthesis of arabinose is FAD dependant two step epimerisation reaction which is catalysed by DprE1 and DprE2 flavoprotein enzymes. The current review is mainly emphases on DprE1 as a perspective challenge for further research.

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

“…Anyhow, to fulfill their reactions it is conceivable that the two enzymes must work in concert, thus, reasonably a strong interaction occurs. In this context, the elucidation of the structural and functional behavior of the full decaprenylphosphoryl-β-d-ribofuranose 2-epimerase complex should be a useful tool for the development of further antitubercular inhibitors [73].…”

SAR Analysis of Small Molecules Interfering with Energy-Metabolism in Mycobacterium tuberculosis

“…Very few molecules make it through the stringent bottlenecks of TB drug discovery because finding a new anti-TB drug is challenging: new compounds should kill Mtb with novel mechanisms of action showing rapid bactericidal activity, as well as activity against bacteria in different metabolic states without host toxicity. Even though the advances in understanding the biology of Mtb, including its complete genome sequence, have provided a platform of a wide range of novel drug targets, most of the compounds discovered in the last few years repeatedly target the cell wall (MmpL3 [ 3 , 4 , 5 , 6 ], DprE1 [ 7 , 8 , 9 ], FadD32 [ 10 ], and Pks13 [ 11 ]), while most of the approximately 625 essential Mtb genes are unexploited. With the approval of bedaquiline, which targets mycobacterial energy production [ 12 ], and delamanid, which targets both cell wall synthesis and energy production, the energy-metabolism in Mtb [ 12 ] has received significant attention in the last decade as a potential target to investigate and develop new antimycobacterial drugs.…”

Mycobacterium tuberculosis DprE1 inhibitor OPC-167832 is active against Mycobacterium abscessus in vitro

“…models (13,17,18). BTZ-043, PBTZ-169, OPC-167832 and TBA-7371 have progressed to phase I or II clinical trials for TB (19).…”