Design, synthesis, and x-ray analysis of a glycoconjugate bound to mycobacterium tuberculosis antigen 85C

Diaa A. Ibrahim, Julie Boucau, Daniel H. Lajiness, Sri Kumar Veleti, Kevin R. Trabbic, Samuel S. Adams, Donald R. Ronning, Steven J. Sucheck

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

Tuberculosis (TB) is a global health threat with nearly 500 000 new cases of multidrug-resistant TB estimated to occur every year, so new drugs are desperately needed. A number of current antimycobacterial drugs work by interfering with the biosynthesis of key components of the mycolylarabinogalactan (mAG). In light of this observation, other enzymes involved in the synthesis of the mAG should also serve as targets for antimycobacterial drug development. One potential target is the Antigen 85 (Ag85) complex, a family of mycolyltransferases that are responsible for the transfer of mycolic acids from trehalose monomycolate (TMM) to the arabinogalactan. Virtual thiophenyl-arabinoside conjugates were docked to antigen Ag85C (PDB code: 1va5) using Glide. Compounds with good docking scores were synthesized by a Gewald synthesis followed by linking to 5-thioarabinofuranosides. The resulting thiophenyl-thioarabinofuranosides were assayed for inhibition of mycoyltransferase activity using a 4-methylumbelliferyl butyrate fluorescence assay. The conjugates showed K i values ranging from 18.2 to 71.0 μM. The most potent inhibitor was soaked into crystals of Mycobacterium tuberculosis antigen 85C and the structure of the complex determined. The X-ray structure shows the compound bound within the active site of the enzyme with the thiophene moiety positioned in the putative α-chain binding site of TMM and the arabinofuranoside moiety within the known carbohydrate-binding site as exhibited for the Ag85B-trehalose crystal structure. Unexpectedly, no specific hydrogen bonding interactions are being formed between the arabinofuranoside and the carbohydrate-binding site of the active site suggesting that the binding of the arabinoside within this structure is driven by shape complementarily between the arabinosyl moiety and the carbohydrate binding site.

Original languageEnglish (US)
Pages (from-to)2403-2416
Number of pages14
JournalBioconjugate Chemistry
Volume23
Issue number12
DOIs
StatePublished - Dec 19 2012

ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Biomedical Engineering
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry

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    Ibrahim, D. A., Boucau, J., Lajiness, D. H., Veleti, S. K., Trabbic, K. R., Adams, S. S., Ronning, D. R., & Sucheck, S. J. (2012). Design, synthesis, and x-ray analysis of a glycoconjugate bound to mycobacterium tuberculosis antigen 85C. Bioconjugate Chemistry, 23(12), 2403-2416. https://doi.org/10.1021/bc3004342