Strategies for the Development of Glycomimetic Drug Candidates

Carbohydrates are a structurally-diverse group of natural products which play an important role in numerous biological processes, including immune regulation, infection, and cancer metastasis. Many diseases have been correlated with changes in the composition of cell-surface glycans, highlighting their potential as a therapeutic target. Unfortunately, native carbohydrates suffer from inherently weak binding affinities and poor pharmacokinetic properties. To enhance their usefulness as drug candidates, ‘glycomimetics’ have been developed: more drug-like compounds which mimic the structure and function of native carbohydrates. Approaches to improve binding affinities (e.g., deoxygenation, pre-organization) and pharmacokinetic properties (e.g., limiting metabolic degradation, improving permeability) have been highlighted in this review, accompanied by relevant examples. By utilizing these strategies, high-affinity ligands with optimized properties can be rationally designed and used to address therapies for novel carbohydrate-binding targets.