Binding Studies on a Library of Induced‐Fit Synthetic Carbohydrate Receptors with Mannoside Selectivity

Abstract

Synthetic carbohydrate receptors could serve as agents for disease detection, drug delivery, or even therapeutics, however, they are rarely used for these applications because they bind weakly and with a preference towards the all-equatorial glucosides that are not prevalent on the cell surface. Herein the binding of 8 receptors with 5 distinct octyloxy pyranosides, which was measured by mass spectrometry and by H NMR titrations in CD Cl at 298 K, is reported, providing binding affinities that vary from ≈10 -10 m . Although the receptors are promiscuous, 1 shows selectivity for β-Man at a ratio of 103:1 β-Man:β-Gal, receptors 2-4 and 6 have preference for α-Man, 5 is selective for β-Gal, and 10 prefers α-Glc (Man=mannose; Gal=galactose, Glc=glucose). A variety of 1D and 2D NMR, and computational techniques were used to determine the thermodynamic binding parameters (ΔH and ΔS ) and the structure of the host-guest complex, revealing that dimeric receptor 10 binds β-Man with increased enthalpy, but a larger entropic penalty than 1. The first-principles modelling suggests that 10⋅β-Man forms an inclusion-type complex where the glycan engages both monomeric subunits of 10 through H-bonding and C-H⋅⋅⋅π interactions. Like natural glycan-binding proteins, these receptors bind pyranosides by accessing multivalent and cooperative interactions, and these studies suggest a new approach towards biomimetic synthetic carbohydrate receptors, where conformational flexibility and promiscuity are incorporated into design.

Regiochemical Effects on the Carbohydrate Binding and Selectivity of Flexible Synthetic Carbohydrate Receptors with Indole and Quinoline Heterocyclic Groups

“…These molecules are intended to bind glycan targets via H‐bonding and C−H⋅⋅⋅π interactions. The binding of the first of these tetrapodal receptors, SCR001 , with monosaccharides was studied in CDCl 3 and CH 2 Cl 2 , which were chosen as solvents to maximize the strength of noncovalent interactions, and SCR001 showed a slight preference for mannosides [38b,c] . Since then, we have made a series of these tetrapodal SCRs that vary the nature of the heterocycle, the binding between the heterocycle and the biaryl core, and the receptor valency [37–38] .…”

Synthesis and Binding of Mannose‐Specific Synthetic Carbohydrate Receptors

“…Towards this goal, our group has developed a series of noncovalent SCRs based upon the biaryl‐tetrapodal receptor SCR001 that is selective towards mannosides—the C2 epimers of glucosides—as a result of multivalent and cooperative binding modes. Subsequently, we explored the role of the bonding and valency of a small library of tetrapodal SCRs on glycan association, and found that subtle changes in both have profound effects on their affinity and selectivity . Further studies revealed that these tetrapodal SCRs inhibit Zika virus entry into Vero and HeLa cells, most likely by interrupting the clathrin‐mediated endocytosis that follows glycan binding.…”

Molecular Interrogation to Crack the Case of O‐GlcNAc

“…Synthetic receptors with modest selectivity and affinity have been designed for glucopyranosides and mannosides . These receptors present similar architectures that include a set of parallel aromatic surfaces (ground and roof) to provide CH−π interactions with carbohydrate CH groups (Figure a) .…”