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Background:
The human gut is loaded with trillions of commensal bacteria that fly under the radar of our
immune system. However in some cases, the human body does not ignore these bacteria and
a variety of illnesses, such as Crohn’s disease, are thought to arise from an inappropriate
response towards these bacteria (1,2). Currently, muramyl dipepetide (MDP) is the smallest
peptidoglycan fragment known to trigger an immune response through its interaction with the
nucleotide-binding oligomerization domain-containing protein 2 (NOD2) (1,2).
Methods:
In order to develop better therapies for such diseases, assays based on bacterial cell wall
derivatives are urgently needed in order to quickly probe the binding specificity of proposed
innate immune receptors. To address this need, a peptidoglycan-based library of disaccharides
will be synthesized and functionalized with an amine handle that can be attached to a NHSactivated plate for both microarray and SPR assays. These assays will allow us to study binding
with known immune receptors.
Results:
A peptidoglycan-based library of disaccharides is currently being synthesized. Each
disaccharide will contain the known immunostimulatory fragment MDP; however, the type of
sugar linked to MDP will be varied with the incorporation of either: N-acetyl-glucosamine, Dgalactose, D-mannose, or D-glucose as the second sugar.
Discussion and Conclusions:
Upon completion of the synthesis, the disaccharides binding will be determined with proteins
Nod1, Nod2, and NALP3. Future directions include, manipulation at the C6-position of MDP to
determine the effect on binding. Consequently, our synthetic route allows for modification of the
C6-position of the MDP substrate.
Funding:
COBRE 1P20GM104316-01A1
References:
(1) Curr. Opin. Biotechnol. 2016, 40, 97-102
(2) JACS, 2012, 134 (33), 13535–13537