Glycosidase Inhibition by Multivalent Presentation of Heparan Sulfate Saccharides on Bottlebrush Polymers,Biomacromolecules

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Glycosidase Inhibition by Multivalent Presentation of Heparan Sulfate Saccharides on Bottlebrush Polymers
Biomacromolecules ( IF 5.5 ) Pub Date : 2017-09-13 00:00:00 , DOI: 10.1021/acs.biomac.7b01049
Eric T. Sletten ₁ , Ravi S. Loka ₁ , Fei Yu ₁ , Hien M. Nguyen ₁

Affiliation

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 IC₅₀ 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.

中文翻译：

硫酸乙酰肝素糖在牙刷聚合物上的多价呈递抑制糖苷酶的作用

我们在这里报告了首次探索将明确定义的糖单元附着到合成聚合物主链上，以抑制糖苷酶。更具体地说，建立了具有硫酸乙酰肝素（HS）二糖的糖聚合物以抑制糖苷酶，乙酰肝素酶，并具有IC ₅₀在低纳摩尔范围（1.05±0.02 nm）内，其值比其单价对应物高1000倍。在计算机上设计了这些糖聚合物的单体部分，以将已建立好的乙酰肝素酶糖基转变为一个抗体位。研究得出的结论是：（1）糖聚合物对乙酰肝素酶具有水解稳定性，（2）更长的聚合物长度可提供更大的抑制作用，（3）由于乙酰肝素酶的活性位点受阻，增加的局部糖类密度（单触感与双触感）可以忽略不计。此外，HS寡糖和多糖的对照说明了多价支架的效力增强。全面的，

更新日期：2017-09-14

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