title: Manipulating the pH response of 2,3-diaminopropionic acid rich peptides to mediate highly effective gene silencing with low-toxicity.
abstract: Cationic amphipathic pH responsive peptides possess high in vitro and in vivo nucleic acid delivery capabilities and function by forming a non-covalent complex with cargo, protecting it from nucleases, facilitating uptake via endocytosis and responding to endosomal acidification by being released from the complex and inserting into and disordering endosomal membranes. We have designed and synthesised peptides to show how Coulombic interactions between ionizable 2,3-diaminopropionic acid (Dap) side chains can be manipulated to tune the functional pH response of the peptides to afford optimal nucleic acid transfer and have modified the hydrogen bonding capabilities of the Dap side chains in order to reduce cytotoxicity. When compared with benchmark delivery compounds, the peptides are shown to have low toxicity and are highly effective at mediating gene silencing in adherent MCF-7 and A549 cell lines, primary human umbilical vein endothelial cells and both differentiated macrophage-like and suspension monocyte-like THP-1 cells.
authors.affiliation: Institute of Pharmaceutical Science, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, UK.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Abbate
authors.forename: Wanling
authors.initials: W
authors.lastname: Liang
authors.forename: Jayneil
authors.initials: J
authors.lastname: Patel
authors.forename: Yun
authors.initials: Y
authors.lastname: Lan
authors.forename: Luigi
authors.initials: L
authors.lastname: Capriotti
authors.forename: Valentina
authors.initials: V
authors.lastname: Iacobucci
authors.forename: Tam T
authors.initials: TT
authors.lastname: Bui
authors.forename: Poulami
authors.initials: P
authors.lastname: Chaudhuri
authors.forename: Laila
authors.initials: L
authors.lastname: Kudsiova
authors.forename: Louic S
authors.initials: LS
authors.lastname: Vermeer
authors.forename: Patrick F L
authors.initials: PF
authors.lastname: Chan
authors.forename: Xiaole
authors.initials: X
authors.lastname: Kong
authors.forename: Alex F
authors.initials: AF
authors.lastname: Drake
authors.forename: Jenny K W
authors.initials: JK
authors.lastname: Lam
authors.forename: Sukhvinder S
authors.initials: SS
authors.lastname: Bansal
authors.forename: A James
authors.initials: AJ
authors.lastname: Mason
mesh_terms: D000595:Amino Acid Sequence; D002460:Cell Line; D045744:Cell Line, Tumor; D003692:Delayed-Action Preparations / Q000737:chemistry*; D004705:Endocytosis; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008969:Molecular Sequence Data; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics / Q000493:pharmacokinetics; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000737:chemistry
chemical_list: D003692:Delayed-Action Preparations; D034741:RNA, Small Interfering; D015091:beta-Alanine; C011757:2,3-diaminopropionic acid
keywords: Endocytosis; Manipulation of pH response; Monocytes; pH responsive peptides; siRNA delivery