title: Incorporation of 2,3-diaminopropionic acid into linear cationic amphipathic peptides produces pH-sensitive vectors.
abstract: Nonviral vectors that harness the change in pH in endosomes, are increasingly being used to deliver cargoes, including nucleic acids, into mammalian cells. Here we present evidence that the pK(a) of the beta-NH(2) in 2,3-diaminopropionic acid (Dap) is sufficiently lowered, when Dap is incorporated into peptides, that its protonation state is sensitive to the pH changes that occur during endosomal acidification. The lowered pK(a) of around 6.3 is stabilized by the increased electron-withdrawing effect of the peptide bonds, by intermolecular hydrogen bonding and from contributions arising from the peptide conformation. These include mixed polar/apolar environments, Coulombic interactions and intermolecular hydrogen bonding. Changes in the charged state are therefore expected between pH 5 and 7, and large-scale conformational changes are observed in Dap-rich peptides, in contrast to analogues containing lysine or ornithine, when the pH is altered through this range. These physical properties confer a robust gene-delivery capability on designed cationic amphipathic peptides that incorporate Dap.
authors.affiliation: King's College London, Pharmaceutical Science Division, 150 Stamford Street, London, SE1 9NH, UK.
authors.forename: Yun
authors.initials: Y
authors.lastname: Lan
authors.forename: Bérangère
authors.initials: B
authors.lastname: Langlet-Bertin
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Abbate
authors.forename: Louic S
authors.initials: LS
authors.lastname: Vermeer
authors.forename: Xiaole
authors.initials: X
authors.lastname: Kong
authors.forename: Kelly E
authors.initials: KE
authors.lastname: Sullivan
authors.forename: Christian
authors.initials: C
authors.lastname: Leborgne
authors.forename: Daniel
authors.initials: D
authors.lastname: Scherman
authors.forename: Robert C
authors.initials: RC
authors.lastname: Hider
authors.forename: Alex F
authors.initials: AF
authors.lastname: Drake
authors.forename: Sukhvinder S
authors.initials: SS
authors.lastname: Bansal
authors.forename: Antoine
authors.initials: A
authors.lastname: Kichler
authors.forename: A James
authors.initials: AJ
authors.lastname: Mason
mesh_terms: D000595:Amino Acid Sequence; D002460:Cell Line; D002942:Circular Dichroism; D011992:Endosomes / Q000378:metabolism; D018014:Gene Transfer Techniques; D006801:Humans; D006860:Hydrogen Bonding; D006863:Hydrogen-Ion Concentration; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry*; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000737:chemistry
chemical_list: D010455:Peptides; D015091:beta-Alanine; C011757:2,3-diaminopropionic acid