Non-Peptidic Cell-Penetrating Motifs for Mitochondrion-Specific Cargo Delivery

Angew Chem Int Ed Engl. 2018 Dec 21;57(52):17183-17188. doi: 10.1002/anie.201811940. Epub 2018 Nov 27.


Mitochondrial dysfunction is linked to a variety of human illnesses, but selective delivery of therapeutics into the mitochondrion is challenging. Now a family of amphipathic cell-penetrating motifs (CPMs) is presented, consisting of four guanidinium groups and one or two aromatic hydrophobic groups (naphthalene) assembled through a central scaffold (a benzene ring). The CPMs and CPM-cargo conjugates efficiently enter the interior of cultured mammalian cells and are specifically localized into the mitochondrial matrix, as revealed by high-resolution confocal microscopy. With a membrane-impermeable peptide as cargo, the CPMs exhibited ≥170-fold higher delivery efficiency than previous mitochondrial delivery vehicles. Conjugation of a small-molecule inhibitor of heat shock protein 90 to a CPM resulted in accumulation of the inhibitor inside the mitochondrial matrix with greatly enhanced anticancer activity. The CPMs showed minimal effect on the viability or the mitochondrial membrane potential of mammalian cells.

Keywords: cell-penetrating motif; cytosolic entry; drug delivery; mitochondrial targeting.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cell Survival / drug effects
  • Cell-Penetrating Peptides / chemical synthesis
  • Cell-Penetrating Peptides / chemistry
  • Cell-Penetrating Peptides / pharmacology*
  • Drug Delivery Systems*
  • HeLa Cells
  • Humans
  • Membrane Potential, Mitochondrial / drug effects
  • Mitochondria / chemistry
  • Mitochondria / drug effects*
  • Molecular Structure


  • Cell-Penetrating Peptides