Abstract
The aberrant presentation of carbohydrates has been linked to a number of diseases, such as cancer metastasis and immune dysregulation. These altered glycan structures represent a target for novel therapies by modulating their associated interactions with neighboring cells and molecules. Although these interactions are highly specific, native carbohydrates are characterized by very low affinities and inherently poor pharmacokinetic properties. Glycomimetic compounds, which mimic the structure and function of native glycans, have been successful in producing molecules with improved pharmacokinetic (PK) and pharmacodynamic (PD) features. Several strategies have been developed for glycomimetic design such as ligand pre-organization or reducing polar surface area. A related approach to developing glycomimetics relies on the bioisosteric replacement of carbohydrate functional groups. These changes can offer improvements to both binding affinity (e.g., reduced desolvation costs, enhanced metal chelation) and pharmacokinetic parameters (e.g., improved oral bioavailability). Several examples of bioisosteric modifications to carbohydrates have been reported; this review aims to consolidate them and presents different possibilities for enhancing core interactions in glycomimetics.
Highlights
The interaction of carbohydrates with proteins and cells is well established to play important roles in biology, from the maintenance of healthy tissue to the progression of diseases
Several examples of bioisosteric modifications to carbohydrates have been reported; this review aims to consolidate them and presents different possibilities for enhancing core interactions in glycomimetics
Examples of bioisosteric modifications are scattered throughout the literature, and this review aims to consolidate them to present a range of possibilities for enhancing core interactions in glycomimetics
Summary
The interaction of carbohydrates with proteins and cells is well established to play important roles in biology, from the maintenance of healthy tissue to the progression of diseases. Ligands engage the protein through only weak interactions, such as H-bonding, metal chelation, salt bridges, and weak hydrophobic interactions Combined, these are typically insufficient in strength to compensate for the high enthalpic desolvation penalties associated with such polar substrates and shallow, solvent-exposed binding sites. To compensate for these weak interactions with native substrates, lectins typically rely on multivalency to enhance affinity in which multiple carbohydrate-binding domains engage simultaneously with multiple ligands on complementary surfaces [10,11,12,13]. Native carbohydrates are susceptible to hydrolysis in both the acidic pH of the gut or by endogenous glycosidases, and methods to slow down their metabolic degradation will improve their suitability as therapeutics Due to their high polar surface area, native carbohydrate ligands are unable to passively permeate the intestinal enterocyte layer and are not orally bioavailable compounds. Potentially therapeutic carbohydrates are further hindered by poor binding kinetics (fast koff rates leading to short residence times) and rapid renal clearance from the circulation
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