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Title: Genomic and bioinformatic studies on bioactive peptides from frog skin secretions
Author: Wu, Di
ISNI:       0000 0004 6496 6883
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2017
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The modern drug industry has advanced to a new frontline. Peptide-based drugs are now seriously considered because of their multifarious structures and high affinity for many targets, as well as the fact that these agents have previously provided natural lead compounds for blockbuster drug development. Amphibian skin secretions are unique sources of bioactive molecules, particularly bioactive peptides. These bioactive peptides, especially antimicrobial peptides, have attracted much attention during the past decades. The disruption and permeabilisation of microbial cell membranes are the most effective ways of antimicrobial peptides to prevent microbes from developing resistance because the composition of microbial membranes is evolutionarily stable, making it less likely to acquire resistance through mutation. This important natural property of antimicrobial peptides represents a fundamental quality for therapeutic potential. To date, more than 2741 naturally occurring active peptides are included into the Antimicrobial Peptide Database and more than one-third of these are from amphibians. In this study, genomic, peptidomic and bioinformatic techniques have been employed to investigate the bioactive peptides from the skin secretions of several species of frogs, the white-lipped giant tree frog, Litoria infrafrenata from Australasia, the green cascade frog, Odorrana livida, from Asia and the Northern tiger-legged monkey leaf frog, Phyllomedusa hypochondrialis, from South America. By isolating skin secretion-derived mRNAs, cDNA libraries were constructed, peptide precursor genes were cloned and their encoded mature peptides were deduced from these genetic templates and their presence in skin secretions confirmed using reverse-phase HPLC, MALDI-TOF MS and MS/MS fragmentation sequencing. The peptides and their modified analogues were chemically-synthesised for evaluating their bioactivities and investigating their initial structure-activity relationships. The synthetic peptides showed varied bioactivities. The native frenatins from L. infrafrenata were found lacking in antimicrobial activity, however, their designed analogues exhibited broad-spectrum antimicrobial activity. The livisin from 0. livida, belonging to the Bowman-Birk like inhibitor family,possessed trypsin inhibitory activities. DLP-PH from P. hypochondrialis, was identified as a prototype of a novel family of AMP, with a potent broad-spectrum antimicrobial activity, especially against Gram-negative bacteria. A moderate anti-biofilm activity was also observed for this peptide. Moreover, DLP-PH exhibited anti-proliferation activity on certain human cancer cell lines without toxicity to normal human cells. Amphibian skin secretion is thus a quite remarkable source for the discovery of diverse novel bioactive peptides, some of which may have great potential in drug discovery and development.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available