1 research outputs found
Glycosidase Inhibition by Multivalent Presentation of Heparan Sulfate Saccharides on Bottlebrush Polymers
We
report herein the first-time exploration of the attachment of
well-defined saccharide units onto a synthetic polymer backbone for
the inhibition of a glycosidase. More specifically, glycopolymers
endowed with heparan sulfate (HS) disaccharides were established to
inhibit the glycosidase, heparanase, with an IC<sub>50</sub> value
in the low nanomolar range (1.05 ± 0.02 nm), a thousand-fold
amplification over its monovalent counterpart. The monomeric moieties
of these glycopolymers were designed in silico to manipulate the well-established
glycotope of heparanase into an inhitope. Studies concluded that (1)
the glycopolymers are hydrolytic stable toward heparanase, (2) longer
polymer length provides greater inhibition, and (3) increased local
saccharide density (monoantennary vs diantennary) is negligible due
to hindered active site of heparanase. Furthermore, HS oligosaccharide
and polysaccharide controls illustrate the enhanced potency of a multivalent
scaffold. Overall, the results on these studies of the multivalent
presentation of saccharides on bottlebrush polymers serve as the platform
for the design of potent glycosidase inhibitors and have potential
to be applied to other HS-degrading proteins