Dipicolylamine/Metal Complexes that Promote Direct Cell-Membrane Penetration of Octaarginine

Bioconjug Chem. 2019 Feb 20;30(2):454-460. doi: 10.1021/acs.bioconjchem.8b00691. Epub 2018 Nov 30.

Abstract

Marked promotion of membrane permeation of a cell-penetrating peptide, octaarginine (R8), was attained by attachment to a single 2,2'-dipicolylamine moiety (DPA-R8) that forms 1:1 complexes with metal ions. Studies using giant unilamellar vesicles demonstrated that DPA targets phospholipids and enhances R8 binding to the membranes in the presence of metal ions. While DPA/Zn(II) complex has been most frequently employed for chelate formation with phosphates, Ni(II) had the most prominent effect on the membrane binding and penetration of DPA-R8. Facile cytosolic distribution of DPA-R8 was also attained in a few minutes in the presence of Ni(II). Analysis of the cellular uptake methods of DPA-R8/Ni(II) suggested the involvement of direct permeation through cell membrane without the use of endocytosis. The applicability of this system to the intracellular delivery of bioactive compounds was exemplified using a peptidomimetic farnesyltransferase inhibitor, FTI277.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amines / chemistry
  • Amines / metabolism
  • Cell Membrane / metabolism
  • Cell Membrane Permeability
  • Cell-Penetrating Peptides / chemistry
  • Cell-Penetrating Peptides / metabolism*
  • Coordination Complexes / chemistry
  • Coordination Complexes / metabolism*
  • Drug Carriers / chemistry
  • Drug Carriers / metabolism*
  • Endocytosis
  • HeLa Cells
  • Humans
  • Methionine / administration & dosage
  • Methionine / analogs & derivatives
  • Methionine / pharmacokinetics
  • Oligopeptides / chemistry
  • Oligopeptides / metabolism*
  • Picolinic Acids / chemistry
  • Picolinic Acids / metabolism
  • Zinc / chemistry
  • Zinc / metabolism

Substances

  • 2,2'-dipicolylamine
  • Amines
  • Cell-Penetrating Peptides
  • Coordination Complexes
  • Drug Carriers
  • FTI 277
  • Oligopeptides
  • Picolinic Acids
  • octaarginine
  • Methionine
  • Zinc