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

• Published in: Angewandte Chemie International Edition Vol. 57; no. 52; pp. 17183 - 17188
• Main Authors: Appiah Kubi, George, Qian, Ziqing, Amiar, Souad, Sahni, Ashweta, Stahelin, Robert V., Pei, Dehua
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 21.12.2018; Wiley Subscription Services, Inc
• Edition: International ed. in English
• Subjects: Anticancer properties; Antitumor activity; Benzene; Cargo; Cell Survival - drug effects; cell-penetrating motif; Cell-Penetrating Peptides - chemical synthesis; Cell-Penetrating Peptides - chemistry; Cell-Penetrating Peptides - pharmacology; Chemistry; Chemistry, Multidisciplinary; Confocal microscopy; Conjugation; cytosolic entry; drug delivery; Drug Delivery Systems; Heat shock proteins; HeLa Cells; Hsp90 protein; Humans; Hydrophobicity; Illnesses; Inhibitors; Mammalian cells; Mammals; Membrane potential; Membrane Potential, Mitochondrial - drug effects; Microscopy; Mitochondria; Mitochondria - chemistry; Mitochondria - drug effects; mitochondrial targeting; Molecular Structure; Naphthalene; Physical Sciences; Science & Technology; Viability; cytosolic entry; PEPTIDES; cell-penetrating motif; drug delivery; RELEASE; mitochondrial targeting; PROBES
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.201811940

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. It does get in: A non‐peptidic cell‐penetrating motif is able to efficiently and specifically deliver small‐molecule and peptidyl cargoes into the mitochondrial matrix of mammalian cells by crossing both plasma and mitochondrial membranes.