Polymeric Iminosugars Improve the Activity of Carbohydrate-Processing Enzymes

Abstract

Multivalent iminosugars have recently emerged as powerful tools to inhibit the activities of specific glycosidases. In this work, biocompatible dextrans were coated with iminosugars to form linear and ramified polymers with unprecedently high valencies (from 20 to 900) to probe the evolution of the multivalent inhibition as a function of ligand valency. This study led to the discovery that polyvalent iminosugars can also significantly enhance, not only inhibit, the enzymatic activity of specific glycoside-hydrolase, as observed on two galactosidases, a fucosidase, and a bacterial mannoside phosphorylase for which an impressive 70-fold activation was even reached. The concept of glycosidase activation is largely unexplored, with a unique recent example of small-molecules activators of a bacterial O-GlcNAc hydrolase. The possibility of using these polymers as "artificial enzyme effectors" may therefore open up new perspectives in therapeutics and biocatalysis.

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

“…Clustering of inhibitory moieties (inhitopes) on multivalent scaffolds has been shown to inhibit glycosidases with high potency. 19–30 Use of the GlcNS(6S) α (1,4)GlcA disaccharide is also advantageous, as it does not contain an iduronic acid unit nor a C(3)-sulfated glucosamine, diminishing cross-bioactivity. 43,59–62 Furthermore, we hypothesize that attachment of this disaccharide to the aglycon polymerizable linker, which disrupts the hydrolytic ability of heparanase and provides π -cation interactions if an aromatic system is employed.…”

“…However, to the best of our knowledge, the use of synthetic polymers have yet to be fully explored. 19,20,30 …”

Multivalency To Inhibit and Discriminate Hexosaminidases

“…The most significant effect was obtained with HexAB with Rp/ n values of 131, 32, and 75 observed for compounds 20 , 21 , and 22 with increasing valency of 2, 4, and 8, respectively. Previously, several studies have found that higher valency does not necessarily correlate with improved multivalent binding avidity for targeted carbohydrate‐binding or carbohydrate‐processing proteins . To improve potency, fine tuning of the spatial distribution of the azepane ligands through altering the scaffold may be a more effective strategy than simply increasing multivalency.…”

Exploring carbonic anhydrase inhibition with multimeric coumarins displayed on a fullerene scaffold

“…Strikingly, a very recent study demonstrated that polymeric iminosugars could improve the enzymatic activity of some glycosyl-hydrolases, and thus act as effectors, not inhibitors. 9 To date, the glycosidase family is the enzyme class for which the largest amount of data on MEI is available. 6,7,9,10 First, it can be concluded that, among all glycosidases assayed, a minority could be inhibited with a significant multivalent effect.…”

“…9 To date, the glycosidase family is the enzyme class for which the largest amount of data on MEI is available. 6,7,9,10 First, it can be concluded that, among all glycosidases assayed, a minority could be inhibited with a significant multivalent effect. Second, MEI seems to be extremely sensitive to the structure of the multimeric inhibitor: the topology, the valency, the structure of the central scaffold and the length/ rigidity of the tether to which each inhibitor is grafted to the scaffold are parameters that need to be fine-tuned in order to observe and optimize a multivalent inhibition.…”