Synthesis, SAR and in vitro evaluation of new cyclic Arg-Gly-Asp pseudopentapeptides containing a s-cis peptide bond as integrin alphavbeta3 and alphavbeta5 ligands

Bioorg Med Chem. 2008 Apr 15;16(8):4262-71. doi: 10.1016/j.bmc.2008.02.080. Epub 2008 Feb 29.

Abstract

The solid-phase synthesis of two diastereomeric cyclic pseudopeptides containing the Arg-Gly-Asp sequence and the dipeptide isostere 2-amino-3-oxotetrahydro-1H-pyrrolizine-7a(5H)-carboxylic acid (GPTM) is described. Competition binding assays to purified alphavbeta3 and alphavbeta5 integrins with respect to [125I]echistatin showed a high inhibitory activity for the (2S,7aS)-GPTM derivative. Effects of the structural constraint induced by the two enantiomeric scaffolds (2R,7aR)-GPTM and (2S,7aS)-GPTM on the conformation of Arg-Gly-Asp sequence have been computationally investigated using as a reference the recently solved X-ray structure of cyclo(Arg-Gly-Asp-d-Phe-[N-Me]Val) in complex with the extracellular fragment of the alphavbeta3 receptor. The computational method disclosed the key role played by a bridging water molecule on differentiating the two ligands by a diverse stabilization of the ligand-protein complex.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Computer Simulation
  • Integrin alphaVbeta3 / metabolism*
  • Integrins / metabolism*
  • Ligands
  • Models, Molecular
  • Molecular Structure
  • Oligopeptides / chemistry*
  • Peptides, Cyclic / chemical synthesis*
  • Peptides, Cyclic / chemistry
  • Peptides, Cyclic / pharmacology*
  • Receptors, Vitronectin / metabolism*
  • Structure-Activity Relationship

Substances

  • Integrin alphaVbeta3
  • Integrins
  • Ligands
  • Oligopeptides
  • Peptides, Cyclic
  • Receptors, Vitronectin
  • integrin alphaVbeta5
  • arginyl-glycyl-aspartic acid