title: Multiple triphenylphosphonium cations shuttle a hydrophilic peptide into mitochondria.
abstract: A variety of diseases are related to mitochondrial dysfunction. Hence, the ability to transport drugs to mitochondria that are otherwise cell impermeable would be of great therapeutic potential. Triphenylphosphonium (TPP) cations have been shown to accumulate in mitochondria when attached to small molecules. Here we report on the consequence of increasing the number of TPP moieties that are covalently linked to a model hydrophilic peptide Hemagglutinin A (HA). By extending the HA peptide with l-lysine amino acids to which the TPP's are covalently linked through the epsilon-amine, we have systematically synthesized the HA peptide with 0-3 TPP's. All peptides were subsequently labeled with FITC at the N-terminus. Cellular uptake and mitochondrial localization of the HA-TPP conjugates in HeLa cells were profoundly augmented with increasing number of TPPs, suggesting that this approach is applicable for the delivery of peptides. Furthermore, confocal microscopy demonstrated that the peptides localize to mitochondria. Importantly, all peptide conjugates did not show apparent toxicity at concentrations that are several orders of magnitude higher than those used for HA peptide delivery.
authors.affiliation: Department of Pharmacology, The Institute for Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Hadassah Ein-Karem, Jerusalem 91120, Israel.
authors.forename: Shareefa E
authors.initials: SE
authors.lastname: Abu-Gosh
authors.forename: Netanel
authors.initials: N
authors.lastname: Kolvazon
authors.forename: Boaz
authors.initials: B
authors.lastname: Tirosh
authors.forename: Israel
authors.initials: I
authors.lastname: Ringel
authors.forename: Eylon
authors.initials: E
authors.lastname: Yavin
mesh_terms: D002412:Cations / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D005434:Flow Cytometry; D016650:Fluorescein-5-isothiocyanate; D006367:HeLa Cells; D006388:Hemagglutinins / Q000378:metabolism*; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D009943:Organophosphorus Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D010446:Peptide Fragments / Q000378:metabolism*; D014320:Triphenylmethyl Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D002412:Cations; D006388:Hemagglutinins; D009943:Organophosphorus Compounds; D010446:Peptide Fragments; D014320:Triphenylmethyl Compounds; D016650:Fluorescein-5-isothiocyanate