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

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

Author information

1
Department of Chemistry and Biochemistry, The Ohio State University, 484 West 12th Avenue, Columbus, OH, 43210, USA.
2
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 575 W Stadium Ave, West Lafayette, IN, 47907, USA.

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.

KEYWORDS:

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

PMID:
30376611
DOI:
10.1002/anie.201811940

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