Multivalent Inhibitors for Carbohydrate‐Processing Enzymes: Beyond the “Lock‐and‐Key” Concept

Gouin, Sébastien G.

doi:10.1002/chem.201402537

Cited by 104 publications

(58 citation statements)

References 58 publications

(56 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

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

Sletten

Loka

et al. 2017

Biomacromolecules

View full text Add to dashboard Cite

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.

show abstract

Section: Resultsmentioning

confidence: 99%

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

Section: Introductionmentioning

confidence: 99%

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

Sletten

Loka

et al. 2017

Biomacromolecules

View full text Add to dashboard Cite

show abstract

“…54,55 It is reasonable to expect that the novel phenomenon uncovered here may not be limited solely to glyco-ND but likely manifested by other multivalent constructs based on alternate scaffolds, NP-based or otherwise. 54,55 It is reasonable to expect that the novel phenomenon uncovered here may not be limited solely to glyco-ND but likely manifested by other multivalent constructs based on alternate scaffolds, NP-based or otherwise.…”

Section: Discussionmentioning

confidence: 95%

Unprecedented inhibition of glycosidase-catalyzed substrate hydrolysis by nanodiamond-grafted O-glycosides

et al. 2015

View full text Add to dashboard Cite

We report herein the unprecedented finding that a-O-glucosides and also a-O-mannosides, when conjugated on nanodiamond particles (ND), are not only stable towards the hydrolytic action of the corresponding matching glycosidases, but are also endowed with the ability to inhibit them. Moreover, conjugation of the O-glycosides to ND (glyco-ND) sees them transformed into inhibitors of mismatching enzymes (for which they do not serve as substrates even when in their monovalent, free form). The effects of the glyco-NDs have been demonstrated on a panel of commercial glycosidases and the inhibition found to be competitive and reversible and not to be related to any denaturation of enzymes by the ND-conjugates. Values for K i in the low micromolar range have been measured for certain glyco-ND (for example, a K i value of 5.5 AE 0.2 mM was measured for the glucopyranosyl-coated NDs against the a-glucosidase from baker's yeast) andfound to depend on both the identity of the enzyme and the glyco-ND. The latter K i value compares well with that obtained for the natural glucosidase inhibitor, 1-deoxynojirimycin (K i of 25 mM against the aglucosidase from baker's yeast under identical assay conditions). The monovalent control O-glycosides was hydrolysed efficiently by the appropriate glycosidase. Glyco-ND bearing 50% loading of O-glycoside as well ND conjugated with both O-glucosides and O-mannosides (mixed) have also been assayed and shown also to inhibit the panel of glycosidases with potencies and selectivities different from those recorded for the 100% loaded ND and also from one another. The impact on factors such as glycotope density and heteromultivalency on inhibition is reminiscent of that typically encountered in carbohydrate-lectin recognition events. The abilities of the glyco-ND to bind, cross-link and aggregate concanavalin A, a lectin known to recognize both a-O-D-mannosides and a-O-D-glucosides, was assessed by a range of methods including an enzyme-linked lectin assay (ELLA), a two-site sandwich ELLA and a turbidimetry assay, respectively and indeed seen to reflect their expected per glycotope affinity enhancements as compared to monovalent controls: the high avidity of the lectin for each respective glycosylated ND particle was consistent with the manifestation of potent multivalent effects driving lectin recognition and binding.

show abstract

“…[13][14] In the case of carbonic anhydrase, only studies on bivalent inhibitors were recently reported.I ndeed, Whiteside'sr esearch group describedi n2 012 the binding of monovalent and bivalent benzene sulfonamide ligandst oasynthetic dimer of carbonic anhydrase.…”

mentioning

confidence: 99%

Fluorescent Silica Nanoparticles with Multivalent Inhibitory Effects towards Carbonic Anhydrases

Touisni

Kanfar

Ulrich

et al. 2015

Chemistry A European J

View full text Add to dashboard Cite

Multifunctional silica nanoparticles decorated with fluorescent and sulfonamide carbonic anhydrase (CA) inhibitors were prepared and investigated as multivalent enzyme inhibitors against the cytosolic isoforms hCA I and II and the transmembrane tumor-associated ones hCA IX and XII. Excellent inhibitory effects were observed with these nanoparticles, with KI values in the low nanomolar range (6.2-0.67 nM) against all tested isozymes. A significant multivalency effect was seen for the inhibition of the monomeric enzymes hCA I and II compared to the dimeric hCA IX and hCA XII isoforms, where no multivalent effect was observed, suggesting that the multivalent binding is occurring through enzyme clustering.

show abstract

Multivalent Inhibitors for Carbohydrate‐Processing Enzymes: Beyond the “Lock‐and‐Key” Concept

Cited by 104 publications

References 58 publications

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

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

Unprecedented inhibition of glycosidase-catalyzed substrate hydrolysis by nanodiamond-grafted O-glycosides

Fluorescent Silica Nanoparticles with Multivalent Inhibitory Effects towards Carbonic Anhydrases

Contact Info

Product

Resources

About