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Decaprenyl-phosphoryl-ribose 2′-epimerase (DprE1): challenging target for antitubercular drug discovery
© The Author(s) 2018
Received: 12 March 2018
Accepted: 19 June 2018
Published: 23 June 2018
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.
Tuberculosis (TB) is a major worldwide concern whose control has become more critical due to HIV and increased multidrug-resistance (MDR-TB) and extensively drug resistance (XDR-TB) strains of Mycobacterium tuberculosis . The need for newer and effective antiTB drugs are more essential. In the previous decade hard efforts have been made to find new leads for TB drug development utilizing both target-based and structure-based methodologies . Here, we have emphasized on few covalent and non-covalent Decaprenyl-phosphoryl-ribose 2′-epimerase (DprE1) inhibitors which might play the important role in most useful antitubercular therapies those are in clinical advancement. DprE1, an enzyme protein associated with a vital step of epimerisation in mycobacterial cell wall biosynthesis .
Mycobacterium tuberculosis is one of the world’s most dreadful human pathogen because of its ability to persist inside humans for longer time period in a clinically inactive state. Roughly 95% of the general population who infected (33% of the worldwide population) built up an inert infection. The current available vaccine, Mycobacterium bovis Bacillus Calmette–Guerin (BCG), is mostly used in recent years. Specifically, this vaccine prevent most serious types of the infection and not from disease. M. tuberculosis stimulates a solid response, however it has advanced to oppose the body’s activities to kill it and regardless of the possibility of underlying disease is effectively controlled, many people built up an inactive infection that can hold on for quite a long time . For example, Aagaard and colleagues  have built up a multistage immunization technique in which the early antigens Ag85B and 6-kDa early secretory antigenic target are joined with the inertness related protein Rv2660c (H56 antibody). In two mouse models of dormant tuberculosis, they demonstrated that, H56 immunization after presentation can control reactivation and altogether bring down the bacterial load contrasted with adjuvant control mice. The discovery of drugs with novel mechanism of action is direly required because of the expanding number of multidrug safe (MDR), which are strains of M. tuberculosis that are resistant to both isoniazid and rifampicin, with or without protection from different medications, broadly XDR and MDR strains additionally resistant to any fluoroquinolone and any of the second-line against TB injectable medications (amikacin, kanamycin, or capreomycin) .
Mycobacteria are resistant to regular antibiotics with the few exceptions of aminoglycosides, rifamycins and fluoroquinolones . General resistance from therapeutic agents is identified with the structure of the mycobacterial cell envelope bringing about low permeability to exogenous factors . Therefore, a few chemotherapeutic operators are active against Mtb were created. After streptomycin—the primary antitubercular agent and 4-aminosalicylic acid in the 1940s, isoniazid was presented in 1952 and still is the significant component of the antibiotic treatment of TB, WHO groups first-line and second-line antitubercular operators relying on their adequacy and resistance .
Decaprenyl-phosphoribose 2′-epimerase (DprE1)
The heteromeric protein decaprenyl-phospho-ribose 2′-epimerase catalyzes the epimerization reaction of decaprenylphosphoryl-d-ribose (DPR) into decaprenylphosphoryl-d-arabinose (DPA) . This reaction occurs through a successive oxidation–reduction involving the intermediate (decaprenylphosphoryl-2-keto-β-d-erythro-pentofuranose, DPX), which is a result of DPR oxidation and a precursor of DPA . This compound is made up of two proteins encoded by the DprE1 and DprE2 genes. DprE1 and DprE2 have been recommended as decaprenylphosphoryl-β-d-ribose oxidase and decaprenylphosphoryl-d-2-keto erythro pentose reductase, separation . Trefzer and collaborators announced the in vitro interpretation of the enzymatic exercises of sanitized recombinant DprE1 and DprE2 orthologous proteins from Mycobacterium smegmatis and exhibited that DprE1 goes about as an oxidase and DprE2 as a reductase . For epimerase activity, a synchronous articulation of the two polypeptides is required .
Crystal structure of DprE1
Three structures of Mycobacterium smegmatis DprE1 have been established in two distinctive groups and one structure contains BTZ043 . The 19 different structures are M. tuberculosis DprE1 solidified, to be specific hexagonal and orthorhombic, in complex with or without inhibitors . DprE1 is represented by the two-domain topology of the vanillyl-liquor oxidase group of oxido-reductases including a FAD-restricting area and the substrate-restricting ares . The monoclinic and hexagonal precious stone structures show an obvious dimer of DprE1. In any case , DprE1 does not dimerise in solution. The cofactor is profoundly covered in the FAD-restricting area, with the isoalloxazine present at the interface of the substrate-restricting space before the substrate-restricting pocket . As contrast to the homologous structure of alditol oxidase, DprE1 does not covalently tie the prosthetic assembly. Intriguingly, the M. smegmatis DprE1 structure has likewise been understood without the FAD cofactor, showing that FAD is inessential for the collapsing of the protein. Electron density in all crystal structures acquired for M. tuberculosis or M. smegmatis .
Inhibitors of DprE1
BTZ043, the lead compound of the benzothiazinone (BTZ) series, was the primary DprE1 inhibitor described and is particularly strong with an in vitro or in vivo minimum inhibitory concentration (MIC) in the nanomolar extend . The mechanism of BTZ043 clarifies its significant strength since it carries on as a suicide substrate for the decreased type of DprE1 . BTZ043 and other BTZ series experience nitroreduction to nitroso derivatives, which particularly frames a covalent adduct with cysteine 387 (C387) in the dynamic site of DprE1, irreversibly hindering the protein . C387 is profoundly saved in orthologous DprE1 chemicals in actinobacteria, aside from in Mycobacterium avium and Mycobacterium aurum where cysteine is supplanted by alanine and serine individually. These transformations present characteristic BTZ protection .
Current status of DprE1 inhibitors
Covalent and non-covalent DprE1inhibitors
Non covalent inhibitors
1,2,4-Triazole containing 1,4-BTZ derivatives
Structural studies of DprE1 in complex with covalent inhibitors
Mycobacterium smegmatis DprE1 was crystallised in complex with BTZ043, revealing insight into the basic principle of the inhibition mechanisms of covalent inhibitors . BTZ043 is a component based covalent inhibitor, which requires the enzymatic action of the protein with the substrate to change over the nitro group of BTZ043 to get the structure of the covalent complex, DprE1 was incubated with BTZ043 and farnesylphosphoryl-d-ribofuranose (FPR; a simple of DPR with a shorter polyprenyl chain filling in as a reasonable chemical substrate) before performing crystallisation trials . BTZ043 is situated in the substrate-restricting pocket before the isoalloxazine ring of FAD and ties covalently to C394 (proportional to C387 in M. tuberculosis). There are no major basic changes between the local complex types of DprE1 . The trifluoromethyl group of BTZ043 is arranged in a hydrophobic pocket framed by side chains of H132, G133, K134, K367, F369 and N385. The piperidine ring of BTZ043 is kept up on each side by the isoalloxazine ring of FAD, and by G117 and V365. The spirocyclic moiety of BTZ043 is situated at the protein surface and needs full electron thickness, bringing about the adaptability of this area of the particle. To be sure, there is just a single van der Waals interaction amongst L363 and the spirocyclic moiety .
In the greater part of the drug resistance mutants inspected, a similar codon of dprE1 was influenced: the cysteine at position 387 was supplanted by serine or glycine codons, separately. The BTZ protection deciding district of dprE1 was profoundly saved in orthologous qualities from different Actinobacteria, aside from that in a couple of situations where Cys387 was replaced by serine or alanine. The comparing microscopic organisms, Mycobacterium avium and Mycobacterium aurum, were observed to be normally resistant to BTZ, in this way supporting the distinguishing proof of DprE1 as the BTZ target . As early metabolic investigations with microscopic organisms or mice demonstrated that the BTZ nitro group could be lessened to an amino group, the S and R enantiomers of the amino groups and the imaginable hydroxylamine middle were incorporated and tried for antimycobacterial action. The amino and hydroxylamine groups were significantly less dynamic regard to the nitro group. Regarding this, a protection mechanism to BTZs was represented in M. smegmatis . The overexpression of the nitroreductase NfnB prompts the inactivation of the medication by lessening of a basic nitro group to an amino group. Some M. smegmatis BTZ-safe mutants which harbored neither changes in MSMEG_6382 (dprE1) nor in MSMEG_6385 (dprE2), however in the MSMEG_6503 quality, coding for a putative transcriptional controller from the TetR family were separated. It unveiled that this controller controls the translation of the MSMEG_6505 quality, coding for NfnB compound. This transformation prompted a flawed repressor, causing overexpression of NfnB and thus, the decrease of the BTZ nitro atom to its less dynamic amino group . To additionally the immediate part of NfnB in the BTZ protection, an in-outline unmarked cancellation was made in the nfnB quality and the ΔnfnB strain was touchy to BTZ .
Structural studies of DprE1 in complex with noncovalent inhibitors
Basic characterization of TCA1 in complex with M. tuberculosis DprE1 uncovered that TCA1 is situated in the focal cavity of DprE1 in a boomerang-like compliance as on account of the covalent inhibitors, with the thiophene moiety arranged somewhere down in the hydro-phobic pocket at the base of the dynamic site . Likewise with the covalent inhibitors, this cooperation has all the earmarks of being vital for the official. Besides, TCA1 is kept up by polar contacts between the carboxamido group and thiazole nitrogen of TCA1 and K418 of M. tuberculosis DprE1 . Additionally, the carbamate moiety forms van der Waals interaction critical for the stabilisation of the compound with the phenyl ring of Y314 .
TBA-7371 (1–4 azaindoles)
1,2,4-Triazole containing 1,4-BTZ derivatives (cmp-6c)
Conclusion and future perspectives
Tuberculosis is one of the potential threat to entire mankind as per the history. The numbers of WHO supports global burden of this infection which is increasing drastically. Among the millions of unexplored targets for antitubercular drug discovery, DprE1 is recently came out. Specifically, Nitro group of synthesized compounds gets reduced to nitroso and then it forms adduct with Cys387 residue to exhibit DprE1 inhibitory activity. Very few amount of protein was isolated and studied for specific inhibitory activity. There are few derivatives which were reported in past decade with potential DprE1 inhibitory activity. Even though they have shown DprE1 inhibition but none of them has passed phase II trials. Those inhibitors were covalent as well as non-covalent too. The situation is alarming, so there is strict need to explore this target by designing novel potential analogues to combat drug resistance Mycobacterium tuberculosis at the earliest to serve the humanity. There is a strong possibility that DprE1 inhibitors might be active against DprE2 because of the crystal structure of enzyme. In future, researchers have wide scope to work on that with two approaches viz., by designing potent DprE1 inhibitors which may acts against DprE2, by comparing mutants in DprE2.
JG perceived the ideas for this manuscript and also wrote the manuscript. CB reviewed regularly, suggested corrections, majors for improvisation. Both authors read and approved the final manuscript.
The authors declare that they have no competing interests.
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