In this thesis, we have shown that functionalization of short peptides with GCP moiety resulted in novel peptide analogues that demonstrated remarkable cellular uptake ability. One of these newly developed peptide analogues, with only two amino acid residues, is the smallest cell penetrating peptide which has been reported. Moreover, we showed that with more GCP modification, the binding process of these peptides with DNA became more enthalpy favored. This might provide a unique strategy to shift the thermodynamic profiles of peptide/DNA binding. Such supramolecular binding motifs not only allow for more specific interactions with the DNA but also with the cell membrane. This enormously enhances the cellular uptake of corresponding peptide/DNA polyplexes relative to peptides with only natural amino acids.
We also synthesized a cyclic peptide with GCP group modification on the side chain of lysine which resulted in a novel cationic peptide nanotube. As far as we know, this is the first example that a positively charged cyclic peptide forms nanotubes under physiological conditions. Moreover, we demonstrated that it can be applied as gene delivery vector. DNA was successfully attached on the surface of nanotubes. The resulted nanotube showed an astonishing ability in gene transfection through non-endocytic cellular uptake pathway.
On the other hand, the first example of artificial peptide forming β-helix structure was described in this thesis. The alternative D and L alanine construction designed to mimic the structure of gramicidin A endowed the helical property. However, in sharp contrast to typical β-helix structures which have been reported so far, the β-helix formation required no involvement of membrane mimics. Characteristic CD signals for β-helix were observed in pure water. Similar structural property can be found in native insect antifreeze proteins (AFP) in which the individual β-sheets were connected with loops to stabilize the β-helix conformation. While in our case, the individual β-sheets were connected by supramolecular recognition motif (GCP+–COO−). In overall, the self-assembly of peptide with GCP modification not only demonstrated the first supramolecular β-helix mimic in water but also highlighted the application of supramolecular recognition motif in constructing secondary structures.
In the last part of thesis, GCP group was introduced into Fmoc-containing dipeptide. Due to its low pKa value, GCP groups facilitated the assembly of peptide into helical fibers in water. In comparison, peptide without GCP modifications did not show any assembling property
|Advisor:||Schmuck , Carsten|
|School:||Universitaet Duisburg-Essen (Germany)|
|Source:||DAI-C 81/1(E), Dissertation Abstracts International|
|Subjects:||Organic chemistry, Chemistry|
|Keywords:||Peptide, Gene delivery vector, Supramolecular assembly|
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