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Discovery, structural modification and biological evaluations of peptides from Phyllomedusa hypochondrialis Shikuan Zheng (24292910) PUREID: 688179280 Peptide Discovery Antimicrobial Peptides Peptide Engineering Dermaseptin Anticancer Peptides Antimicrobial peptides (AMP) have attracted widespread attention due to their antimicrobial and anticancer activities. However, their clinical translation is frequently hindered by limited potency, poor selectivity and susceptibility to environmental conditions. This thesis systematically explores multiple peptide-engineering strategies to optimise amphibian-derived peptides. First, a novel Dermaseptin-family AMP, Dermaseptin-HL (HL), was identified from Phyllomedusa hypochondrialis skin secretion and shown to possess potent broad-spectrum antibacterial activity, rapid membrane-disruptive kinetics, and strong anticancer effects. Then, a truncation strategy was employed to facilitate structural modification of HL and investigate structure–activity relationships. The truncation studies on HL and its homologue Dermaseptin H6 (H6) revealed that C-terminal hydrophobic segments and α-helical stability are essential for sustaining antimicrobial potency, whereas shortening the peptide can reduce toxicity but frequently compromises activity. 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> 2026-10-01T16:13:15Z Text Thesis 10.17034/32805767.v1 https://figshare.com/articles/thesis/Discovery_structural_modification_and_biological_evaluations_of_peptides_from_Phyllomedusa_hypochondrialis/32805767 All Rights Reserved Open Access after 2031-07-31