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Incorporation of 2,3‐Diaminopropionic Acid into Linear Cationic Amphipathic Peptides Produces pH‐Sensitive Vectors
Author(s) -
Lan Yun,
LangletBertin Bérangère,
Abbate Vincenzo,
Vermeer Louic S.,
Kong Xiaole,
Sullivan Kelly E.,
Leborgne Christian,
Scherman Daniel,
Hider Robert C.,
Drake Alex F.,
Bansal Sukhvinder S.,
Kichler Antoine,
Mason A. James
Publication year - 2010
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201000073
Subject(s) - chemistry , protonation , cationic polymerization , endosome , hydrogen bond , amphiphile , peptide , intermolecular force , biophysics , micelle , lysine , amino acid , stereochemistry , biochemistry , combinatorial chemistry , organic chemistry , molecule , biology , aqueous solution , ion , copolymer , intracellular , polymer
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 p K a of the β‐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 p K 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.