Control of Multivalent Interactions by Binding Epitope Density

Abstract

Receptor clustering by multivalent ligands can activate signaling pathways. In principle, multivalent ligand features can control clustering and the downstream signals that result, but the influence of ligand structure on these processes is incompletely understood. Using a series of synthetic polymers that vary systematically, we studied the influence of multivalent ligand binding epitope density on the clustering of a model receptor, concanavalin A (Con A). We analyze three aspects of receptor clustering: the stoichiometry of the complex, rate of cluster formation, and receptor proximity. Our experiments reveal that the density of binding sites on a multivalent ligand strongly influences each of these parameters. In general, high binding epitope density results in greater numbers of receptors bound per polymer, faster rates of clustering, and reduced inter-receptor distances. Ligands with low binding epitope density, however, are the most efficient on a binding epitope basis. Our results provide insight into the design of ligands for controlling receptor-receptor interactions and can be used to illuminate mechanisms by which natural multivalent displays function.

Synthetic Multivalent Ligands as Probes of Signal Transduction

“…[46,165] Importantly, this polymerization method allows control over the RE display and density. [166,167] The differences in activity between these compounds can, therefore, be attributed to specific aspects of ligand structure.…”

“…[168][169][170][171][172][173] Similarly, libraries of multivalent ligands might be expected to contain compounds that possess diverse activities. [119][120][121]166,167,174] However, the potential diversity of multivalent materials is great and strategies to synthesize diverse collections of multivalent ligands are only beginning to emerge.…”

“…Combinatorial approaches to multivalent ligand synthesis are in their infancy: Only a few synthetic strategies for generating diverse multivalent ligands have been described. [119][120][121]166,167,174] [153] Future advances in synthetic methods and purification technologies will be instrumental in providing multivalent materials with broad architectural diversity.…”

Stimuli‐responsive polypeptide materials prepared by ring‐opening polymerization of α‐amino acid N‐carboxyanhydrides

“…It has four sugar binding sites, which can specifically bind with mannose and glucose. 61,62 In particular, Recently, great progress has been made with synthetic glycolpolypeptides, which might mimic glycosylated peptides and proteins in nature. The Deming group firstly synthesized well-defined glycopolypeptides through direct ROP of glycolated amino acids based on lysine 64 and cysteine.…”

Rigid Multivalent Scaffolds Based on Adamantane

“…10 A scaffold for the assembly of multivalent ligands must therefore orient the ligands in a defined and proper geometry for binding. [11][12][13] This geometry, along with other design criteria (such as the number of ligands, solubility, biocompatibility) may vary for different applications and in consequence, a variety of different scaffolds has been used in the past. 14-17…”