The Impact of Heteromultivalency in Lectin Recognition and Glycosidase Inhibition: An Integrated Mechanistic Study

Abstract

The vision of multivalency as a strategy limited to achieve affinity enhancements between a protein receptor and its putative sugar ligand (glycotope) has proven too simplistic. On the one hand, binding of a glycotope in a dense glycocalix-like construct to a lectin partner has been shown to be sensitive to the presence of a third sugar entity (heterocluster effect). On the other hand, several carbohydrate processing enzymes (glycosidases and glycosyltransferases) have been found to be also responsive to multivalent presentations of binding partners (multivalent enzyme inhibition), a phenomenon first discovered for iminosugar-type inhibitory species (inhitopes) and recently demonstrated for multivalent carbohydrate constructs. By assessing a series of homo- and heteroclusters combining α-d-glucopyranosyl-related glycotopes and inhitopes, it was shown that multivalency and heteromultivalency govern both kinds of events, allowing for activation, deactivation or enhancement of specific recognition phenomena towards a spectrum of lectin and glycosidase partners in a multimodal manner. This unified scenario originates from the ability of (hetero)multivalent architectures to trigger glycosidase binding modes that are reminiscent of those harnessed by lectins, which should be considered when profiling the biological activity of multivalent architectures.

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

“…4,73 Furthermore, we hypothesize that placement of a secondary sugar moiety in such close proximity enhances the probability of statistical rebinding and can also force a secondary unit into other binding sites, thus, allowing 6 to bind to both heparin binding domains (HBD-1 and HBD-2). 20,23,6770 Additionally, the diantennary unit potentially mimics the trisaccharide that binds into the −1/−2/+1 subsites of heparanase, but removes the scissile bond, thereby preventing cleavage by bridging over the catalytic residues. 31,32 Knowing the desire for a homogeneous polymer with uniform distribution of the pendant saccharides, a grafting-through method of polymerization was to be used.…”

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

Multivalent Thiosialosides and Their Synergistic Interaction with Pathogenic Sialidases

“…To summarize, the design of polymerict hiosialosides led to highly potent sialidase inhibitors with high synergistic multivalent effects. Binding affinitiesw ere significantly increased with sialidase lectin domains, but strong inhibition of the enzymatic activity was observed on the catalytic domain.T he design of multivalent glycosidase modulators is ap romising emerging field, [39][40][41][42][43] as illustrated by the continuousr eports of potent glycosidase activators [44,45] and inhibitors based on clusterized iminosugars [46][47][48][49] or sugar substrates. [50] Thisconcept is now extendedt ot he inhibition of bacterial and pathogenics ialidases, for which transition-state inhibitors fail to reach the sub-micromolar level.…”

Giant Glycosidase Inhibitors: First‐ and Second‐Generation Fullerodendrimers with a Dense Iminosugar Shell

“…[9,[16][17][18] In 2010, the fielde xperienced am ajor breakthrough with the discoveryo fi nhibition potencye nhancements towards the a-mannosidase from Jack beans of three orders of magnitude for ad odecavalent fullereneC 60 -based iminosugar cluster when compared to ac ontrol monomer. Astep ahead, such binding modes can be ad-ditionallys witched on or off by homo-and heteromultivalent systemse xposing inhitopes and/org lycotopes, [27] leading to the formulation of a" generalized multivalent effect concept". [24] The identification of sp 2 -iminosugar glycomimetics [25] with the capability to bind simultaneously to glycosidasesa nd lectins in av alency-dependentm anner providedu seful tools for mechanistic studies.…”