Heather L. Handl

Hitting multiple targets with multimeric ligands.

Multimeric ligands consist of multiple monomeric ligands attached to a single backbone molecule, creating a multimer that can bind to multiple receptors or targets simultaneously. Numerous examples of multimeric binding exist within nature. Due to the multiple and simultaneous binding events, multimeric ligands bind with an increased affinity compared to their corresponding monomers. Multimeric ligands may provide opportunities in the field of drug discovery by providing enhanced selectivity and affinity of binding interactions, thus providing molecular-based targeted therapies. However, gaps in our knowledge currently exist regarding the quantitative measures for important design characteristics, such as flexibility, length and orientation of the inter-ligand linkers, receptor density and ligand sequence. In this review, multimeric ligand binding in two separate phases is examined. The prerecruitment phase describes the binding of one ligand of a multimer to its corresponding receptor, an event similar to monomeric ligand binding. This results in transient increases in the local concentration of the other ligands, leading to apparent cooperativity. The postrecruitment phase only occurs once all receptors have been aligned and bound by their corresponding ligand. This phase is analogous to DNA–DNA interactions in that the stability of the complex is derived from physical orientation. Multiple factors influence the kinetics and thermodynamics of multimeric binding, and these are discussed.

Heterobivalent Ligands Crosslink Multiple Cell-Surface Receptors: The Human Melanocortin-4 and δ-Opioid Receptors†

Cell-surface receptor mediated signaling is mechanistically complex. Hetero- and homo-multimerization of receptors appears to occur naturally and is a significant regulatory component of signal transduction.[1] Additionally, exogenous entities, such as cells and viruses, can interact with multiple heterologous receptors and induce clustering.[2] Such multivalent interactions are characterized by enhanced affinities (avidities) relative to monovalent binding and enhanced specificities with heteromultivalent interactions. For example, polymers containing α-MSH (α-melanocyte stimulating hormone) ligands bind with higher affinity to melanoma cells compared to monovalent α-MSH ligands.[3–5] Recapitulation of these natural phenomena using synthetic multivalent agents has been proposed for many years.[3–9] Although homomultivalent agents are known, there is little precedent for synthetic heteromultivalent targeting of cell-surface receptors. Herein we detail the synthesis and bioevaluation of heterobivalent ligands (htBVLs) targeted to two heterologous cell-surface receptors.

Heterobivalent Ligands Crosslink Multiple Cell-Surface Receptors ― A Step Towards Personal Medicine

Introduction Effective treatment of tumor malignancies depends upon identifying targets – molecular markers that differentiate cancer cells from healthy cells. Current cancer therapies involve targeting either differential metabolism, especially nucleic acid biosynthesis pathways, or overexpressed specific gene products. We propose an alternative approach – to specifically target combinations of cell-surface receptors using heteromultivalent ligands (htMVLs). We envision that a three cell-surface protein combination that is expressed on a cancer cell but not on a normal cell could be targeted with heteromultivalent ligands displaying cognate binding motifs of weak affinities. These constructs should bind with high avidity and specificity to cancer population in vivo [1, 2]. As a proof-of-concept, we have synthesized series of heterobivalent constructs of MSH, CCK and -opioid receptors (Fig. 1). The constituent binding motifs in these constructs were moderately potent (see Fig. 1 legend) and were connected via a semi-rigid poly(Pro-Gly) linker flanked by flexible polyethylene glycol based PEGO chains.