Rational improvement of the affinity and selectivity of integrin binding of grafted lasso peptides

J Med Chem. 2014 Jul 10;57(13):5829-34. doi: 10.1021/jm5004478. Epub 2014 Jun 27.

Abstract

Integrins moderate diverse important functions in the human body and are promising targets in cancer therapy. Hence, the selective inhibition of specific integrins is of great medicinal interest. Here, we report the optimization of a grafted lasso peptide, yielding MccJ25(RGDF), which is a highly potent and selective αvβ3 integrin inhibitor. Furthermore, its NMR structure was elucidated and employed in a molecular dynamics approach, revealing information about the integrin binding mode and selectivity profile of MccJ25(RGDF).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bacteriocins / genetics
  • Cell Adhesion / drug effects
  • Human Umbilical Vein Endothelial Cells / drug effects
  • Humans
  • Integrin alphaVbeta3 / antagonists & inhibitors*
  • Integrin alphaVbeta3 / chemistry
  • Models, Molecular
  • Molecular Dynamics Simulation
  • Nuclear Magnetic Resonance, Biomolecular
  • Peptides / chemistry*
  • Peptides / pharmacology
  • Protein Conformation
  • Snake Venoms / pharmacology

Substances

  • Bacteriocins
  • Integrin alphaVbeta3
  • Peptides
  • Snake Venoms
  • microcin
  • Cilengitide

Associated data

  • PDB/1L5G
  • PDB/1Q71
  • PDB/2MMT
  • PDB/2MMW