4-Aminoproline-based arginine-glycine-aspartate integrin binders with exposed ligation points: practical in-solution synthesis, conjugation and binding affinity evaluation

Org Biomol Chem. 2009 Dec 7;7(23):4924-35. doi: 10.1039/b914836a. Epub 2009 Oct 6.

Abstract

An expedient and practical in-solution synthesis of three new 4-aminoproline-based arginine-glycine-aspartate integrin binders--compounds 15, 17 and 19--is presented. Two candidates carrying exposed azide and amine functional points were further advanced to trimeric platform 21 as well as fluorescein- and DOTA-conjugates 23 and 25. The new compounds were assayed for their binding affinity towards human alpha(V)beta3 and alpha(V)beta5 integrin receptors. Both monomeric candidates and covalent conjugates revealed potent ligand competence for the alpha(V)beta3 receptor in the one-digit nanomolar range (IC50 alpha(V)beta3 = 0.2-8.0 nM; IC50 alpha(V)beta5 = 5.0-1621 nM), thus demonstrating that conjugation does not impair the exquisite binding profile of this new generation of integrin ligands.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Humans
  • Integrins / chemistry*
  • Molecular Conformation
  • Oligopeptides / chemistry*
  • Proline / analogs & derivatives*
  • Proline / chemistry
  • Solutions
  • Stereoisomerism

Substances

  • Integrins
  • Oligopeptides
  • Solutions
  • aminoproline
  • arginyl-glycyl-aspartic acid
  • Proline