Journal
CHEMBIOCHEM
Volume 11, Issue 9, Pages 1266-1272Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cbic.201000073
Keywords
circular dichroism; gene delivery; NMR spectroscopy; peptides; pH sensitivity
Funding
- Medical Research Council
- Wellcome Trust
- University of London
- Medical Research Council [G0801072] Funding Source: researchfish
- MRC [G0801072] Funding Source: UKRI
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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-NH2 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 Daprich 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.
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