Designing Multivalent Ligands to Control Biological Interactions: From Vaccines and Cellular Effectors to Targeted Drug Delivery

Abstract

Multivalent interactions in which multiple ligands on one object bind to multiple receptors on another are commonly found in natural biological systems. In addition, these interactions can lead to increased strength and selectivity when compared to the corresponding monovalent interaction. These attributes have also guided the design of synthetic multivalent ligands to control biological interactions. This review will highlight the recent literature describing the use of multivalent ligand display in the design of vaccines, immunomodulators, cell signaling effectors, and vehicles for targeted drug delivery.

Nanostructure Empowers Active Tumor Targeting in Ligand‐Based Molecular Delivery

“…Multivalent ligands generally show lower dissociation rates than individual versions ligands in the interaction with the receptor, apart from a cooperative cell binding that promotes a more efficient early interaction and endosomal internalization . Such cooperativity in both signaling and internalization of artificial constructs has been already described in different therapeutic platforms, what could be specially efficient in the case of symmetrically ordered materials . In the case of recombinant proteins, multivalent presentation of ligands in supramolecular constructs might be more efficient than monovalent versions, what has been already discussed in the context of virus‐like presentations of cell interactors and the consequent enhanced endosomal cell uptake .…”

“…While the role of nanostructure as an element influencing passive targeting has been largely discussed and recognized, its potential impact on active targeting (that mediated by a cell‐surface ligand) has been a rather neglected issue. Nanoscale organization of a targeted material might enhance its interaction with target cells by the multimeric binding of nanoparticles to cell surface receptor molecules . Multivalent ligands generally show lower dissociation rates than individual versions ligands in the interaction with the receptor, apart from a cooperative cell binding that promotes a more efficient early interaction and endosomal internalization .…”

Bifunctional chemical probes inducing protein–protein interactions

“…Notable are systems where monovalent interactions can be weak on their own, e.g. carbohydrate binding elements and cell surface receptors [82], and where multiple domains are available for multivalent recognition of post-translational modifications, such as chromatin binding proteins [83]. Finding compounds that induce cellular PPIs with functional consequences remains a historic challenge.…”

Crystal structures of peanut lectin in the presence of synthetic β-N- and β-S-galactosides disclose evidence for the recognition of different glycomimetic ligands

“…Nevertheless, the observed interaction reflects the fact that not only the recognition element but also the carbohydrate scaffold may present additional binding interactions with the lectin residues or the water network at the ligand-binding pocket, enhancing the ligand affinity. Historically, carbohydrate-based scaffolds have not been extensively investigated compared with dendrimers or polymers (Kiessling et al, 2006;Arsiwala et al, 2019). However, sugar scaffolds have previously shown promising properties for the design of multivalent glycoclusters, based on improved hydrophilicity and pharmacokinetics, compared with peptidic, aromatic or polymeric scaffolds (Gouin et al, 2007).…”