1 research outputs found
Design, Synthesis, and X‑ray Analysis of a Glycoconjugate Bound to Mycobacterium tuberculosis Antigen 85C
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 <i>K</i><sub>i</sub> 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