title: Biodistribution of intracellularly acting peptides conjugated reversibly to Tat.
abstract: Intracellularly acting peptide modulators of signaling enzymes provide a powerful means to regulate signaling events. Delivery of peptides into cells is facilitated by conjugation to carrier peptides, such as Tat. When peptides are irreversibly conjugated to Tat, Tat-mediated subcellular localization may predominate, resulting in mislocalization of the peptide cargo. We have used intracellularly acting peptides, conjugated to Tat by a disulfide bond, to modulate protein kinase C (PKC) signaling; these PKC-modulating peptides are released from Tat upon intracellular delivery. Previously, the distribution of these peptides within tissue and throughout the body had not been demonstrated. We show here intravascular delivery of a PKC-peptide, reversibly conjugated to Tat, resulted in distribution throughout cardiac tissue. In addition, a single injection resulted in selective modulation of PKC activity in many organs. Therefore, intracellularly acting peptide modulators of signaling enzymes, reversibly conjugated to Tat, have extensive biodistribution and can be used to modulate signaling pathways in vivo.
authors.affiliation: Department of Molecular Pharmacology, Stanford University School of Medicine, Stanford University, Stanford, CA 94305-5174, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Begley
authors.forename: Tamar
authors.initials: T
authors.lastname: Liron
authors.forename: Jeremy
authors.initials: J
authors.lastname: Baryza
authors.forename: Daria
authors.initials: D
authors.lastname: Mochly-Rosen
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001692:Biological Transport; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives / Q000378:metabolism; D015696:Gene Products, tat / Q000737:chemistry / Q000493:pharmacokinetics*; D007274:Injections, Intraperitoneal; D007527:Isoenzymes; D009206:Myocardium / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D014018:Tissue Distribution; D014966:Xanthenes / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D015696:Gene Products, tat; D007527:Isoenzymes; D010455:Peptides; D014966:Xanthenes; C034657:Texas red; D011493:Protein Kinase C; D016650:Fluorescein-5-isothiocyanate