(R-X-R)4 -Motif Peptides Containing Conformationally Constrained Cyclohexane-Derived Spacers: Effect on Cellular Uptake

ChemMedChem. 2017 Nov 8;12(21):1743-1747. doi: 10.1002/cmdc.201700498. Epub 2017 Oct 13.

Abstract

Arginine-rich peptides having the (R-X-R)n motif are among the most effective cell-penetrating peptides (CPPs). Herein we report a several-fold increase in the efficacy of such CPPs if the linear flexible spacer (-X-) in the (R-X-R) motif is replaced by constrained cyclic 1,4-substituted-cyclohexane-derived spacers. Internalization of these oligomers in mammalian cell lines was found to be an energy-dependent process. Incorporation of these constrained, non-proteinogenic amino acid spacers in the CPPs is shown to enhance their proteolytic stability.

Keywords: (R-X-R)-motif; cell-penetrating peptides; cellular uptake; protease stability.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Survival / drug effects
  • Cell-Penetrating Peptides / chemistry
  • Cell-Penetrating Peptides / pharmacology
  • Circular Dichroism
  • Cyclohexanes / chemistry*
  • Erythrocytes / cytology
  • Erythrocytes / drug effects
  • Erythrocytes / metabolism
  • HeLa Cells
  • Hemolysis / drug effects
  • Humans
  • Microscopy, Confocal
  • Peptides / chemistry*
  • Peptides / metabolism
  • Peptides / pharmacology
  • Protein Stability

Substances

  • Cell-Penetrating Peptides
  • Cyclohexanes
  • Peptides