title: Therapeutic design of peptide modulators of protein-protein interactions in membranes.
abstract: Membrane proteins play the central roles in a variety of cellular processes, ranging from nutrient uptake and signalling, to cell-cell communication. Their biological functions are directly related to how they fold and assemble; defects often lead to disease. Protein-protein interactions (PPIs) within the membrane are therefore of great interest as therapeutic targets. Here we review the progress in the application of membrane-insertable peptides for the disruption or stabilization of membrane-based PPIs. We describe the design and preparation of transmembrane peptide mimics; and of several categories of peptidomimetics used for study, including d-enantiomers, non-natural amino acids, peptoids, and β-peptides. Further aspects of the review describe modifications to membrane-insertable peptides, including lipidation and cyclization via hydrocarbon stapling. These approaches provide a pathway toward the development of metabolically stable, non-toxic, and efficacious peptide modulators of membrane-based PPIs. This article is part of a Special Issue entitled: Lipid order/lipid defects and lipid-control of protein activity edited by Dirk Schneider.
authors: Division of Molecular Structure & Function, Research Institute, Hospital for Sick Children, Toronto M5G 0A4, Ontario, Canada; Department of Biochemistry, University of Toronto, Toronto M5S 1A8, Ontario, Canada.
authors: Tracy A
authors: TA
authors: Stone
authors: Division of Molecular Structure & Function, Research Institute, Hospital for Sick Children, Toronto M5G 0A4, Ontario, Canada; Department of Biochemistry, University of Toronto, Toronto M5S 1A8, Ontario, Canada. Electronic address: deber@sickkids.ca.
authors: Charles M
authors: CM
authors: Deber
mesh_terms: D020816:Amino Acid Motifs; D001249:Asthma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D008563:Membrane Lipids / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D057786:Peptidomimetics / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D034444:Peptoids / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D000072756:Protein Conformation, alpha-Helical; D000072757:Protein Conformation, beta-Strand; D017510:Protein Folding; D013237:Stereoisomerism
chemical_list: D008563:Membrane Lipids; D008565:Membrane Proteins; D010456:Peptides, Cyclic; D057786:Peptidomimetics; D034444:Peptoids
keywords: Hydrocarbon staple; Lipidation; Peptide; Peptidomimetics; Protein–protein interaction (PPI); Transmembrane