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

George Appiah Kubi, Ziqing Qian, Souad Amiar, Ashweta Sahni, Robert V. Stahelin, Dehua Pei

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)17183-17188
Number of pages6
JournalAngewandte Chemie - International Edition
Volume57
Issue number52
DOIs
StatePublished - Dec 21 2018

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Keywords

  • cell-penetrating motif
  • cytosolic entry
  • drug delivery
  • mitochondrial targeting

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)

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