Glycomimetic Drugs: Source of Novel Therapeutics

Abstract

Complex carbohydrates contain dense structural information that is decoded in recognition processes among cells, their pathogens and products, as well as many other functional proteins and represent a new source of novel therapeutics. Native carbohydrate ligands, however, lack classic drug-like properties and in general suffer from poor pharmacokinetics, bioavailability, stability, and low affinity. One solution is to rationally design glycomimetic drugs based on the bioactive conformation of the native carbohydrate ligand obtained from empirical data using techniques such as STD-NMR and X-ray crystallography. Modifications to improve binding affinity include stabilizing the bioactive core structure thereby reducing entropy costs of the interaction as well as adding second site interactions to enhance enthalpic contributions. Improvements in bioavailability and pharmacokinetics can be realized by lowering the molecular weight, reducing polar surface area and hydrogen bond donors and acceptors, as well as increasing log P. Examples of approved glycomimetic drugs are discussed and highlight the great potential of using this technology to uncover an entire class of innovative drugs to address current unmet medical needs.