Design and synthesis of glycomimetics: Recent advances

Abstract

In the past few decades, our understanding of glycan information‐encoding power has notably increased, thus leading to a significant growth also in the design and synthesis of glycomimetic probes. Combining data from multiple analytical sources, such as crystallography, nuclear magnetic resonance spectroscopy, and other biophysical methods (eg, surface plasmon resonance and carbohydrate microarrays) has allowed to shed light on the key interaction events between carbohydrates and their protein‐targets. However, the low metabolic stability of carbohydrates and their high hydrophilicity, which translates in low bioavailability, undermine their development as drugs. In this framework, the design of chemically modified analogues (called carbohydrate mimics or glycomimetics) appears as a valid alternative for the development of therapeutic agents. Glycomimetics, as structural and functional mimics of carbohydrates, can replace the native ligands in the interaction with target proteins, but are designed to show enhanced enzymatic stability and bioavailability and, possibly, an improved affinity and selectivity toward the target. In the present account, we specifically focus on the most recent advances in the design and synthesis of glycomimetics. In particular, we highlight the efforts of the scientific community in the development of straightforward synthetic procedures for the preparation of sugar mimics and in their preliminary biological evaluation.

BC2L-C N-Terminal Lectin Domain Complexed with Histo Blood Group Oligosaccharides Provides New Structural Information

“…Lectins play a key role in microbial adhesion to host cells and between bacterial cells during biofilm formation, hence, antiadhesive glycodrugs or glycomimetics inhibiting lectins are attracting increasing attention as novel antimicrobials [12,13]. In this context, and due to its affinity for human oligosaccharides, BC2L-CN becomes a relevant target.…”

A stabilized glycomimetic conjugate vaccine inducing protective antibodies against Neisseria meningitidis serogroup A

“…Strategies for the chemical or enzymatic synthesis of natural MenA structures have been proposed 25,26 . Differently from these approaches, we envisaged the use of synthetic chemistry to generate stabilized MenA glycomimetics 27,28 . Mimics, in which structural changes are implemented to improve specific features of the natural polysaccharide have so far not been incorporated in conjugate vaccines inducing protective immune responses 29 .…”

Synthesis of New Series of 2-C-(β-D-glucopyranosyl)-Pyrimidines and Their Evaluation as Inhibitors of Some Glycoenzymes

“…C-Glycopyranosyl heterocycles [1] are among the widely investigated groups of sugar-based small molecules. The intense interest in such compounds is primarily due to their possible use as glycomimetics [1][2][3]. The hydrolitically stable C-C linkage between the glycon and the heterocyclic aglycon part, and the ability of the heteroaromatic moiety to strengthen the binding by diverse interactions (e.g., hydrogen bonds, van der Waals interactions, π-π stackings, and coordination to metal ions) to target biomolecules, along with some general advantages derived from the presence of the sugar component (e.g., enhancement of the solubility, the possibility of targeting carbohydrate binding proteins), make these compounds very attractive in drug design [4].…”