AbstractFrog skin can produce secretions containing complex chemical components in a holocrine manner. On the one hand, these chemical molecules play an important role in the physiological functions and defence systems of frogs. On the other hand, they provide the main source for the development of new drugs. In this thesis, two naturally occurring Bowman-Birk type inhibitors from skin secretions of frogs were studied together with several rational designed analogues.
In Chapter 3, a novel potent Bowman-Birk type inhibitor PPF-BBI was discovered and identified in the skin secretions of the Fukien gold-striped pond frog (Pelophylax plancyi fukienensis), belong to the pLR/Ranacyclin family. PPF-BBI and K16-PPF-BBI displayed excellent trypsin and tryptase inhibitory activity and antimicrobial activity. When the lysine residue at P1 site was replaced by phenylalanine, the forming peptide F8-BBI-PPF exhibited strong chymotrypsin inhibitory activity but totally lost the trypsin inhibitory activity. In Chapter 4, pLR-HR, which has an identical sequence with a known histamine-releasing peptide pLR, was studied with its related analogues. The chymotrypsin inhibitory activity of pLR-HR and QUB-1879 was found due to the residue of P2’ site. QUB-2084 and QUB-2085 were proven the significant effects of P2’ site and C-terminal amidation. The truncated analogue, QUB-1879 showed better bioactivity on protease inhibition and anti-proliferation. In addition, negligible LDH releasing was observed when treated by QUB-1879. In Chapter 5, the trypsin inhibitory loop was linked to Tat49-57 to improve the biological activities and bioavailability. Tat-loop has both trypsin inhibitory activity and antifungal activity with extremely low cytotoxicity on erythrocytes and normal human cells.
|Date of Award||Dec 2019|
|Supervisor||Tianbao Chen (Supervisor), Mei Zhou (Supervisor), James Burrows (Supervisor) & Roberta Burden (Supervisor)|