engleski

Dimeric Analogue of a Natural Antimicrobial Peptide with Improved Activity and Selectivity: A Study Connecting Bioinformatics, Biophysics and Biochemistry

As a part of the innate immune system, antimicrobial peptides (AMPs) are mostly inactive against eukaryotic cells at antimicrobial concentrations. This insensitivity is generally attributed to the different lipid composition of the prokaryotic and eukaryotic membranes. Because of their net positive charge, AMPs are primarily attracted by anionic bacterial membranes. The therapeutic index (TI) of AMPs is often defined as the ratio of MIC over HC50, where HC50 is peptide concentration needed to reach 50% lysis of red blood cells while antimicrobial activity is expressed as minimal inhibitory concentration (MIC) for bacterial growth. TI is a measure of peptide’s selectivity. The higher TI the more selective is the AMP. Besides being experimentally determined, TI can be also predicted by using dedicated tool for TI prediction of amphibian- derived helical AMPs (http://split4.pmfst.hr/split/dserv1/). Naturally occurring AMPs present a good template for the design of novel peptides with the aim of achieving improved antimicrobial potency and selectivity. Knowledge-based Mutator algorithm http://split4.pmfst.hr/mutator/ can suggest analogues of natural AMPs with improved properties. The question asked in this thesis is will sequential dimmer of weakly active natural frog-derived peptide exhibit better activity and selectivity when its design is guided with TI- predictor and Mutator algorithm. The DAP peptide was synthesized and shown to have a far better activity against E. coli than the monomer. The obtained value for its selectivity is excellent (TI>150) and supports future research in this area.

antimicrobial peptide; sequential dimmer; therapeutic index; mutator algorithm

magistarski rad (MSc thesis)