Influencing receptor-ligand binding mechanisms with multivalent ligand architecture

J Am Chem Soc. 2002 Dec 18;124(50):14922-33. doi: 10.1021/ja027184x.

Abstract

Multivalent ligands can function as inhibitors or effectors of biological processes. Potent inhibitory activity can arise from the high functional affinities of multivalent ligand-receptor interactions. Effector functions, however, are influenced not only by apparent affinities but also by alternate factors, including the ability of a ligand to cluster receptors. Little is known about the molecular features of a multivalent ligand that determine whether it will function as an inhibitor or effector. We envisioned that, by altering multivalent ligand architecture, ligands with preferences for different binding mechanisms would be generated. To this end, a series of 28 ligands possessing structural diversity was synthesized. This series provides the means to explore the effects of ligand architecture on the inhibition and clustering of a model protein, the lectin concanavalin A (Con A). The structural parameters that were varied include scaffold shape, size, valency, and density of binding elements. We found that ligands with certain architectures are effective inhibitors, but others mediate receptor clustering. Specifically, high molecular weight, polydisperse polyvalent ligands are effective inhibitors of Con A binding, whereas linear oligomeric ligands generated by the ring-opening metathesis polymerization have structural properties that favor clustering. The shape of a multivalent ligand also influences specific aspects of receptor clustering. These include the rate at which the receptor is clustered, the number of receptors in the clusters, and the average interreceptor distance. Our results indicate that the architecture of a multivalent ligand is a key parameter in determining its activity as an inhibitor or effector. Diversity-oriented syntheses of multivalent ligands coupled with effective assays that can be used to compare the contributions of different binding parameters may afford ligands that function by specific mechanisms.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Chemical Precipitation
  • Concanavalin A / antagonists & inhibitors
  • Concanavalin A / chemistry
  • Concanavalin A / metabolism
  • Ligands*
  • Models, Molecular
  • Molecular Weight
  • Polymers / chemistry
  • Receptors, Cell Surface / antagonists & inhibitors
  • Receptors, Cell Surface / chemistry*
  • Receptors, Cell Surface / metabolism
  • Serum Albumin, Bovine / antagonists & inhibitors
  • Serum Albumin, Bovine / chemistry
  • Serum Albumin, Bovine / metabolism

Substances

  • Ligands
  • Polymers
  • Receptors, Cell Surface
  • Concanavalin A
  • Serum Albumin, Bovine