title: Peptidomimetic modification improves cell permeation of bivalent farnesyltransferase inhibitors.
abstract: Bivalent enzyme inhibitors, in which a surface binding module is linked to an active site binding module through a spacer, are a robust approach for site-selectively delivering a minimally-sized agent to a protein surface to regulate its functions, such as protein-protein interactions (PPIs). Previous research revealed that these agents effectively disrupt the interaction between farnesyltransferase (FTase) and the C-terminal region of K-Ras4B protein. However, the whole cell activity of these peptide-based agents is limited due to their low membrane permeability. In this study, we tested a peptidomimetic modification of these bivalent agents using a previously developed inhibitor, FTI-249, and evaluated their cell permeability and biological activity in cells. Confocal cell imaging using fluorescently-labeled agents showed that the peptidomimetic 3-BODIPY penetrated cells, while the peptide-based 1-BODIPY did not. Cell-based evaluation demonstrated that peptidomimetic 3 at a concentration of 100μM inhibited HDJ-2 processing in cells, indicating that this peptidomimetic modification improves cell permeability, thus leading to enhanced whole cell activity of the bivalent compounds.
authors.affiliation: The Institute of Scientific and Industrial Research, Osaka University, 8-1 Mihogaoka, Ibaraki, Osaka 567-0047, Japan.
authors.forename: Shinnosuke
authors.initials: S
authors.lastname: Machida
authors.forename: Mai
authors.initials: M
authors.lastname: Tsubamoto
authors.forename: Nobuo
authors.initials: N
authors.lastname: Kato
authors.forename: Kazuo
authors.initials: K
authors.lastname: Harada
authors.forename: Junko
authors.initials: J
authors.lastname: Ohkanda
mesh_terms: D045744:Cell Line, Tumor; D057846:Cell-Penetrating Peptides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D051231:Farnesyltranstransferase / Q000737:chemistry / Q000378:metabolism*; D005456:Fluorescent Dyes; D006801:Humans; D018613:Microscopy, Confocal; D057786:Peptidomimetics / Q000737:chemistry
chemical_list: D057846:Cell-Penetrating Peptides; D004791:Enzyme Inhibitors; D005456:Fluorescent Dyes; D057786:Peptidomimetics; D051231:Farnesyltranstransferase