Synthetic Multivalent Ligands as Probes of Signal Transduction

Abstract

Cell surface receptors acquire information from the extracellular environment and coordinate intracellular responses. Evidence from biochemical and structural studies indicates that many receptors do not operate as individual entities, but rather as part of higher-order complexes (e.g. dimers and oligomers). Coupling the functions of multiple receptors may endow signaling pathways with the sensitivity and malleability required to govern cellular responses. Moreover, multireceptor signaling complexes may provide a means of spatially segregating otherwise degenerate signaling cascades. Despite the proposed importance of receptor-receptor processes in cellular signaling, questions concerning the mechanisms, extent, and consequences of receptor co-localization and interreceptor communication remain unanswered.Chemical synthesis can provide a variety of compounds with which to address the role of receptor assembly in signal transduction. The focus of this review is one such approach -the use of synthetic multivalent ligands to characterize receptor function. Multivalent ligands can be generated that possess a variety of sizes, shapes, valencies, orientations, and densities of binding elements. Their unique architectures imbue multivalent ligands with the ability to access binding modes not available to monovalent compounds. Multivalent ligands, therefore, are capable of illuminating aspects of inter-receptor processes that are not readily probed using conventional approaches. We suggest that, as focus shifts from investigations of the function of individual proteins and toward the analysis of multi-receptor signaling complexes, multivalent ligands will become even more valuable tools with which to ask sophisticated mechanistic questions. Further, multivalent ligands may provide new opportunities for manipulating receptor systems for the deconvolution of pathways, diagnosis, and, ultimately, the treatment of disease.

Structure, function, self-assembly, and applications of bottlebrush copolymers

“…Bottlebrush polymers have a high density of chain ends and might also be useful as synthetic multivalent ligands for coupling to cell surface receptors 130 .…”

Site-Directed Conjugation of “Clicked” Glycopolymers To Form Glycoprotein Mimics: Binding to Mammalian Lectin and Induction of Immunological Function

“…3, [13][14][15] For ligand comparative studies it is therefore of importance to have a set of synthetic tools that allows for the synthesis of libraries of polymers having identical macromolecular features, with the relative density of epitope binding units being the only variable. Postpolymerization processes appear to be the only way for achieving this goal as long as extremely efficient grafting processes are available.…”

Multiplexing Ligand−Receptor Binding Measurements by Chemically Patterning Microfluidic Channels

“…2 Examination of the underlying thermodynamics of ligandreceptor binding may lead to a greater understanding of its biological role and could provide insight into biomedical applications involving inhibitory drug design. 1,3,4 Unfortunately, high-throughput, low-protein consumption assays are not presently well enough developed in this field to afford rapid, systematic studies of binding data at two-dimensionally fluid bilayer interfaces. 5 In previous work it has been demonstrated that microfluidic devices can be designed for measuring binding affinities in multivalent systems.…”