2015
DOI: 10.1021/acs.jmedchem.5b00719
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Targeting Mycobacterium tuberculosis Biotin Protein Ligase (MtBPL) with Nucleoside-Based Bisubstrate Adenylation Inhibitors

Abstract: Mycobacterium tuberculosis (Mtb) responsible for both latent and symptomatic tuberculosis (TB) remains the second leading cause of mortality among infectious diseases worldwide. Mycobacterial biotin protein ligase (MtBPL) is an essential enzyme in Mtb and regulates lipid metabolism through the post-translational biotinylation of acyl coenzyme A carboxylases. We report the synthesis and evaluation of a systematic series of potent nucleoside-based inhibitors of MtBPL that contain modifications to the ribofuranos… Show more

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Cited by 39 publications
(36 citation statements)
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“…We previously reported the design and characterization of potent inhibitors of biotin protein ligase (BPL), the enzyme responsible for covalently ligating biotin onto the ACCs (12)(13)(14)(15)(16)(17)(18)(19). This led to 5′-[N-(d-biotinoyl)sulfamoyl]amino-5′-deoxyadenosine (Bio-AMS), a BPL inhibitor with potent on-target whole-cell activity against drugsensitive and drug-resistant Mtb (17).…”
Section: Introductionmentioning
confidence: 99%
“…We previously reported the design and characterization of potent inhibitors of biotin protein ligase (BPL), the enzyme responsible for covalently ligating biotin onto the ACCs (12)(13)(14)(15)(16)(17)(18)(19). This led to 5′-[N-(d-biotinoyl)sulfamoyl]amino-5′-deoxyadenosine (Bio-AMS), a BPL inhibitor with potent on-target whole-cell activity against drugsensitive and drug-resistant Mtb (17).…”
Section: Introductionmentioning
confidence: 99%
“…In this regard, the African flora represents a valuable source of anti-infectious compounds to be exploited as drugs [ 5 , 6 , 7 ]. In the fight against Trypanosoma infections, new therapeutic options can be provided by plant extracts, essential oils, and plant-borne compounds [ 6 , 8 , 9 , 10 ]. Essential oils are volatile mixtures distilled from aromatic plants and composed of several dozens of components such as terpenoids, phenylpropanoids, and aliphatic compounds [ 11 , 12 ].…”
Section: Introductionmentioning
confidence: 99%
“…Quantification by LC-MS has been utilized by others to rationalize differences in inhibitor potency between enzyme assays and in cellulo experiments. 37, 38 Using a protocol developed by Chatterji and coworkers, 39 we evaluated compound accumulation in M. smegmatis , upon treatment with 25 μM of either 1 or 2 . The level of cell-associated 2 was approximately 14-fold higher than that of 1 .…”
mentioning
confidence: 99%