Design of a bioactive cell-penetrating peptide: when a transduction domain does more than transduce

J Pept Sci. 2009 Oct;15(10):668-74. doi: 10.1002/psc.1168.


The discovery of cell-penetrating peptides (CPPs) has facilitated delivery of peptides into cells to affect cellular behavior. Previously, we were successful at developing a phosphopeptide mimetic of the small heat shock-like protein HSP20 . Building on this success we developed a cell-permeant peptide inhibitor of mitogen-activated protein kinase-activated protein kinase 2 (MK2). It is well documented that inhibition of MK2 may be beneficial for a myriad of human diseases including those involving inflammation and fibrosis. During the optimization of the activity and specificity of the MK2 inhibitor (MK2i) we closely examined the effect of cell-penetrating peptide identity. Surprisingly, the identity of the CPP dictated kinase specificity and functional activity to an extent that rivaled that of the therapeutic peptide. The results reported herein have wide implications for delivering therapeutics with CPPs and indicate that judicious choice of CPP is crucial to the ultimate therapeutic success.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Cell Survival
  • Cells, Cultured
  • Drug Design
  • Epithelial Cells
  • HSP20 Heat-Shock Proteins / chemistry*
  • Humans
  • Inhibitory Concentration 50
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
  • Molecular Sequence Data
  • Peptides / chemical synthesis*
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinases / metabolism
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*


  • HSP20 Heat-Shock Proteins
  • Intracellular Signaling Peptides and Proteins
  • Peptides
  • Protein Kinase Inhibitors
  • Protein Kinases
  • MAP-kinase-activated kinase 2
  • Protein-Serine-Threonine Kinases