Cyclodextrin (CD) history has been largely dominated by their unique ability to form inclusion complexes with guests fitting in their hydrophobic cavity. Chemical funcionalization was soon recognized as a powerful mean for improving CD applications in a wide range of fields, including drug delivery, sensing or enzyme mimicking. However, 100 years after their discovery, CDs are still perceived as novel nanoobjects of undeveloped potential. This critical review provides an overview of different strategies to promote interactions between CD conjugates and genetic material by fully exploiting the inside-outside/upper-lower face anisotropy of the CD nanometric platform. Covalent modification, self-assembling and supramolecular ligation can be put forward with the ultimate goal to build artificial viruses for programmed and efficient gene therapy (222 references).

Covalent attachment of biorecognizable sugar ligands in several copies at precise positions of cyclomaltooligosaccharide (cyclodextrin, CD) macrocycles has proven to be an extremely flexible strategy to build multivalent conjugates. The commercial availability of the native CDs in three different sizes, their axial symmetry and the possibility of position- and face-selective functionalization allow a strict control of the valency and spatial orientation of the recognition motifs (glycotopes) in low, medium, high and hyperbranched glycoclusters, including glycodendrimer–CD hybrids. “Click-type” ligation chemistries, including copper(I)-catalyzed azide–alkyne cycloaddition (CuAAC), thiol–ene coupling or thiourea-forming reactions, have been implemented to warrant full homogeneity of the adducts. The incorporation of different glycotopes to investigate multivalent interactions in heterogeneous environments has also been accomplished. Not surprisingly, multivalent CD conjugates have been, and continue to be, major actors in studies directed at deciphering the structural features ruling carbohydrate recognition events. Nanometric glycoassemblies endowed with the capability of adapting the inter-saccharide distances and orientations in the presence of a receptor partner or capable of mimicking the fluidity of biological membranes have been conceived by multitopic inclusion complex formation, rotaxanation or self-assembling. Applications in the fields of sensors, site-specific drug and gene delivery or protein stabilization attest for the maturity of the field.

Despite efficiently imitating functional ligand presentations in terms of valency and density, most of the reported multivalent carbohydrate prototypes barely reflect the inherent heterogeneity of biological systems, therefore underestimating the potential contribution of synergistic or antagonistic effects to molecular recognition events. To address this question, the design of novel molecular and supramolecular entities displaying different saccharide motifs in a controlled manner is of critical importance. In this review we highlight the current efforts made to synthesize heteromultivalent glycosystems on different platforms (peptides, dendrimers, polymers, oligonucleotides, calixarenes, cyclodextrins, microarrays, vesicles) and to evaluate the influence of heterogeneity in carbohydrate–protein (lectin, antibody) recognition phenomena. Although the number of publications on this topic is limited as compared to the huge volume of reports on homomultivalent sugar displays, the current body of results has already unravelled the existence of new binding mechanisms that operate in heterogeneous environments whose exact biological significance remains to be unveiled.

Lysosomal storage disorders (LSDs) are often caused by mutations that destabilize native folding and impair the trafficking of enzymes, leading to premature endoplasmic reticulum (ER)-associated degradation, deficiencies of specific hydrolytic functions and aberrant storage of metabolites in the lysosomes. Enzyme replacement therapy (ERT) and substrate reduction therapy (SRT) are available for a few of these conditions, but most remain orphan. A main difficulty is that virtually all LSDs involve neurological decline and neither proteins nor the current SRT drugs can cross the blood–brain barrier. Twenty years ago a new therapeutic paradigm better suited for neuropathic LSDs was launched, namely pharmacological chaperone (PC) therapy. PCs are small molecules capable of binding to the mutant protein at the ER, inducing proper folding, restoring trafficking and increasing enzyme activity and substrate processing in the lysosome. In many LSDs the mutated protein is a glycosidase and the accumulated substrate is an oligo- or polysaccharide or a glycoconjugate, e.g. a glycosphingolipid. Although it might appear counterintuitive, substrate analogues (glycomimetics) behaving as competitive glycosidase inhibitors are good candidates to perform PC tasks. The advancements in the knowledge of the molecular basis of LSDs, including enzyme structures, binding modes, trafficking pathways and substrate processing mechanisms, have been put forward to optimize PC selectivity and efficacy. Moreover, the chemical versatility of glycomimetics and the variety of structures at hand allow simultaneous optimization of chaperone and pharmacokinetic properties. In this Feature Article we review the advancements made in this field in the last few years and the future outlook through the lessons taught by three archetypical LSDs: Gaucher disease, G_M1-gangliosidosis and Fabry disease.