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Title: 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. Herein, 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 KDs ≤ 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.

Authors:
 [1];  [1];  [1];  [1];  [2];  [1];  [1];  [2];  [2];  [2];  [1];  [1]
  1. Univ. of Minnesota, Minneapolis, MN (United States)
  2. Weill Cornell Medical College, New York, NY (United States)
Publication Date:
Research Org.:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
National Institutes of Health (NIH); Cancer Center Support Grant; Industrial Macromolecular Crystallography Association
OSTI Identifier:
1241056
Grant/Contract Number:  
AI091790; S10-OD017982; CA-77598
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Journal of Medicinal Chemistry
Additional Journal Information:
Journal Volume: 58; Journal Issue: 18; Journal ID: ISSN 0022-2623
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
ENGLISH
Subject:
60 APPLIED LIFE SCIENCES; Nutrition; Inhibitors; Lipids; Organic compounds; Ligands

Citation Formats

Bockman, Matthew R., Kalinda, Alvin S., Petrelli, Riccardo, De la Mora-Rey, Teresa, Tiwari, Divya, Liu, Feng, Dawadi, Surendra, Nandakumar, Madhumitha, Rhee, Kyu Y., Schnappinger, Dirk, Finzel, Barry C., and Aldrich, Courtney C. Targeting Mycobacterium tuberculosis Biotin Protein Ligase (MtBPL) with Nucleoside-Based Bisubstrate Adenylation Inhibitors. United States: N. p., 2015. Web. doi:10.1021/acs.jmedchem.5b00719.
Bockman, Matthew R., Kalinda, Alvin S., Petrelli, Riccardo, De la Mora-Rey, Teresa, Tiwari, Divya, Liu, Feng, Dawadi, Surendra, Nandakumar, Madhumitha, Rhee, Kyu Y., Schnappinger, Dirk, Finzel, Barry C., & Aldrich, Courtney C. Targeting Mycobacterium tuberculosis Biotin Protein Ligase (MtBPL) with Nucleoside-Based Bisubstrate Adenylation Inhibitors. United States. https://doi.org/10.1021/acs.jmedchem.5b00719
Bockman, Matthew R., Kalinda, Alvin S., Petrelli, Riccardo, De la Mora-Rey, Teresa, Tiwari, Divya, Liu, Feng, Dawadi, Surendra, Nandakumar, Madhumitha, Rhee, Kyu Y., Schnappinger, Dirk, Finzel, Barry C., and Aldrich, Courtney C. 2015. "Targeting Mycobacterium tuberculosis Biotin Protein Ligase (MtBPL) with Nucleoside-Based Bisubstrate Adenylation Inhibitors". United States. https://doi.org/10.1021/acs.jmedchem.5b00719. https://www.osti.gov/servlets/purl/1241056.
@article{osti_1241056,
title = {Targeting Mycobacterium tuberculosis Biotin Protein Ligase (MtBPL) with Nucleoside-Based Bisubstrate Adenylation Inhibitors},
author = {Bockman, Matthew R. and Kalinda, Alvin S. and Petrelli, Riccardo and De la Mora-Rey, Teresa and Tiwari, Divya and Liu, Feng and Dawadi, Surendra and Nandakumar, Madhumitha and Rhee, Kyu Y. and Schnappinger, Dirk and Finzel, Barry C. and Aldrich, Courtney C.},
abstractNote = {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. Herein, 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 KDs ≤ 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.},
doi = {10.1021/acs.jmedchem.5b00719},
url = {https://www.osti.gov/biblio/1241056}, journal = {Journal of Medicinal Chemistry},
issn = {0022-2623},
number = 18,
volume = 58,
place = {United States},
year = {Thu Sep 03 00:00:00 EDT 2015},
month = {Thu Sep 03 00:00:00 EDT 2015}
}

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journal, November 2018


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