title: Protein Mimicry and the Design of Bioactive Cell-Penetrating Peptides.
abstract: The multi-domain architecture of many human proteins provides a structural basis for the physical maintenance of interactomes, or networks of protein-protein interactions (PPIs), that are so obviously crucial to cellular functions. Moreover, the structural and electrostatic complementarity provided by PPI interfaces, predominantly located on protein surfaces, is a fundamental component of signal transduction events that are known to be compromised in human diseases including many cancers.The pharmacokinetic advantages provided by cell-penetrating peptides (CPPs) are entirely compatible with the development of intrinsically permeable agents capable of modulating intracellular PPIs. Thus, the term bioportide is a useful descriptor of numerous bioactive CPPs that are distinct from the more usual inert CPP vectors. Herein we illustrate a generic strategy, predominantly centered upon the identification of cationic peptides derived from helical protein domains, which offers a reliable platform to identify bioportides capable of modulating intracellular signal transduction events. In addition, we describe robust methodologies to determine the precise intracellular distribution of fluorescent bioportides and present assays routinely employed to screen for the detrimental pharmacodynamic properties often exhibited by both CPPs and bioportides; namely adverse cytotoxicity and the receptor-independent stimulation of mast cell secretion.
authors.affiliation: Research Institute in Healthcare Science, Faculty of Science and Engineering, University of Wolverhampton, Wulfruna Street, Wolverhampton, WV1 1DJ, UK, J.Howl@wlv.ac.uk.
authors.forename: John
authors.initials: J
authors.lastname: Howl
authors.forename: Sarah
authors.initials: S
authors.lastname: Jones
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D032701:Biomimetics / Q000379:methods; D057846:Cell-Penetrating Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism*; D060326:Chemistry Techniques, Synthetic / Q000379:methods; D006801:Humans; D008407:Mast Cells / Q000737:chemistry / Q000166:cytology / Q000378:metabolism; D018613:Microscopy, Confocal / Q000379:methods; D008856:Microscopy, Fluorescence / Q000379:methods; D008958:Models, Molecular; D008969:Molecular Sequence Data; D025941:Protein Interaction Mapping / Q000379:methods; D060066:Protein Interaction Maps; D017433:Protein Structure, Secondary; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction; D001619:beta-N-Acetylhexosaminidases / Q000378:metabolism
chemical_list: D057846:Cell-Penetrating Peptides; D011506:Proteins; D001619:beta-N-Acetylhexosaminidases