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J Med Chem. 2015 Sep 24;58(18):7349-7369. doi: 10.1021/acs.jmedchem.5b00719. Epub 2015 Sep 3.

Targeting Mycobacterium tuberculosis Biotin Protein Ligase (MtBPL) with Nucleoside-Based Bisubstrate Adenylation Inhibitors.

Author information

1
Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455, USA.
2
Center for Drug Design, Academic Health Center, University of Minnesota, MN 55455 USA.
3
Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY 10021, USA.
#
Contributed equally

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 ribofuranosyl ring of the nucleoside. All compounds were characterized by isothermal titration calorimetry (ITC) and shown to bind potently with K(D)s ≤ 2 nM. Additionally, we obtained high-resolution cocrystal structures for a majority of the compounds. Despite fairly uniform biochemical potency, the whole-cell Mtb activity varied greatly with minimum inhibitory concentrations (MIC) ranging from 0.78 to >100 μM. Cellular accumulation studies showed a nearly 10-fold enhancement in accumulation of a C-2'-α analogue over the corresponding C-2'-β analogue, consistent with their differential whole-cell activity.

PMID:
26299766
PMCID:
PMC4667793
DOI:
10.1021/acs.jmedchem.5b00719
[Indexed for MEDLINE]
Free PMC Article

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