title: Activation and inhibition of G protein-coupled receptors by cell-penetrating membrane-tethered peptides.
abstract: Classical ligands bind to the extracellular surface of their cognate receptors and activate signaling pathways without crossing the plasma membrane barrier. We selectively targeted the intracellular receptor-G protein interface by using cell-penetrating membrane-tethered peptides. Attachment of a palmitate group to peptides derived from the third intracellular loop of protease-activated receptors-1 and -2 and melanocortin-4 receptors yields agonists and/or antagonists of receptor-G protein signaling. These lipidated peptides--which we have termed pepducins--require the presence of their cognate receptor for activity and are highly selective for receptor type. Mutational analysis of both intact receptor and pepducins demonstrates that the cell-penetrating agonists do not activate G proteins by the same mechanism as the intact receptor third intracellular loop but instead require the C-tail of the receptor. Construction of such peptide-lipid conjugates constitutes a new molecular strategy for the development of therapeutics targeted to the receptor-effector interface.
authors.affiliation: Molecular Cardiology Research Institute, Division of Hematology/Oncology, New England Medical Center, 750 Washington Street, Boston, MA 02111, USA.
authors.forename: Lidija
authors.initials: L
authors.lastname: Covic
authors.forename: Amy L
authors.initials: AL
authors.lastname: Gresser
authors.forename: Joyce
authors.initials: J
authors.lastname: Talavera
authors.forename: Steven
authors.initials: S
authors.lastname: Swift
authors.forename: Athan
authors.initials: A
authors.lastname: Kuliopulos
mesh_terms: D000595:Amino Acid Sequence; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D044463:Receptor, PAR-1; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D018179:Receptors, Thrombin / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D010455:Peptides; D044463:Receptor, PAR-1; D011956:Receptors, Cell Surface; D018179:Receptors, Thrombin; D019204:GTP-Binding Proteins