Discovery, structural modification and biological evaluations of peptides from Phyllomedusa hypochondrialis

In order to increase the selectivity of AMPs, a novel TPP conjugated cyclopeptide scaffold was designed. The scaffold facilitated intracellular delivery of inactive HL-26, which was subsequently activated by overexpressed glutathione in tumour cells. The results demonstrated that the TPP-CHL26C have an 8-fold increase in therapeutic windows with the parent peptide HL-26 and two different anti-proliferation models for this scaffold were discovered.

Finally, Hyposin-HA3 (HA3) as a template peptide to demonstrate that hydrophobic substitution can increase activity but also increase toxicity. In contrast, introducing a single LPS-binding motif markedly strengthened LPS binding ability and antibacterial activity while maintaining low cytotoxicity. In summary, this study reports a complete experience from a novel lack of selectivity Dermaseptin family peptide to a highly selective peptide.

The innovative design integrates terminal disulphide cyclisation with TPP conjugation to create a novel scaffold for linear peptides, providing a feasible strategy for developing highly-selective anticancer peptides from amphibian-derived AMPs. Different modification strategies were also evaluated by using the template peptide. These rational modification strategies provide new insights for the future engineering of Dermaseptin-based peptides.<br><br><i>Thesis is embargoed until 31 July 2031.</i>