Reseptregisteret 2007–2011 : The Norwegian Prescription Database 2007–2011

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Antimicrobial Activity of Short Analogues of the Marine Peptide EeCentrocin 1: Synthesis of Lipopeptides and Head-to-Tail Cyclic Peptides and Mechanism of Action Studies

We have synthesised a series of 12-residue analogues of a previously reported lead peptide (P6) developed from the heavy chain of the marine peptide EeCentrocin 1, isolated from the sea urchin Echinus esculentus. We optimised the lead peptide by increasing its net positive charge, its lipophilicity through N-terminal fatty acid acylation or incorporation of a Trp residue, and by synthesising head-to- tail cyclic peptides under pseudo–high-dilution conditions. All peptides were screened for antimicrobial and antifungal activity, and toxicity was determined against human red blood cells. The two most potent peptide analogues were the linear peptide P6-W6R8 and its head-to-tail cyclic analogue cP6-W6R8 displaying minimum inhibitory concentrations of 0.4–6.6 μM against Gram-positive and Gram-negative bacteria and 6.2–13 μM against fungi. All peptides showed low haemolytic activity except for two of the lipopeptides, in which haemolytic activity correlated with increasing acyl chain length. Mode of action studies using bacterial biosensor strains revealed a membrane disruptive effect of both the linear and the cyclic peptide. Overall, the results of our study demonstrated that relatively simple structural modifications could be successfully employed in the development of potent antimicrobial lead peptides derived from marine natural products

Reseptregisteret 2007-2011. Tema: Legemidler og eldre / The Norwegian Prescription Database 2007–2011. Topic: Drug use in the elderly

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Antimicrobial activity of small synthetic peptides based on the marine peptide turgencin A: Prediction of antimicrobial peptide sequences in a natural peptide and strategy for optimization of potency

Turgencin A, a potent antimicrobial peptide isolated from the Arctic sea squirt Synoicum turgens, consists of 36 amino acid residues and three disulfide bridges, making it challenging to synthesize. The aim of the present study was to develop a truncated peptide with an antimicrobial drug lead potential based on turgencin A. The experiments consisted of: (1) sequence analysis and prediction of antimicrobial potential of truncated 10-mer sequences; (2) synthesis and antimicrobial screening of a lead peptide devoid of the cysteine residues; (3) optimization of in vitro antimicrobial activity of the lead peptide using an amino acid replacement strategy; and (4) screening the synthesized peptides for cytotoxic activities. In silico analysis of turgencin A using various prediction software indicated an internal, cationic 10-mer sequence to be putatively antimicrobial. The synthesized truncated lead peptide displayed weak antimicrobial activity. However, by following a systematic amino acid replacement strategy, a modified peptide was developed that retained the potency of the original peptide. The optimized peptide StAMP-9 displayed bactericidal activity, with minimal inhibitory concentrations of 7.8 µg/mL against Staphylococcus aureus and 3.9 µg/mL against Escherichia coli, and no cytotoxic effects against mammalian cells. Preliminary experiments indicate the bacterial membranes as immediate and primary targets

Antimicrobial Activity of Small Synthetic Peptides Based on the Marine Peptide Turgencin A: Prediction of Antimicrobial Peptide Sequences in a Natural Peptide and Strategy for Optimization of Potency

Turgencin A, a potent antimicrobial peptide isolated from the Arctic sea squirt Synoicum turgens, consists of 36 amino acid residues and three disulfide bridges, making it challenging to synthesize. The aim of the present study was to develop a truncated peptide with an antimicrobial drug lead potential based on turgencin A. The experiments consisted of: (1) sequence analysis and prediction of antimicrobial potential of truncated 10-mer sequences; (2) synthesis and antimicrobial screening of a lead peptide devoid of the cysteine residues; (3) optimization of in vitro antimicrobial activity of the lead peptide using an amino acid replacement strategy; and (4) screening the synthesized peptides for cytotoxic activities. In silico analysis of turgencin A using various prediction software indicated an internal, cationic 10-mer sequence to be putatively antimicrobial. The synthesized truncated lead peptide displayed weak antimicrobial activity. However, by following a systematic amino acid replacement strategy, a modified peptide was developed that retained the potency of the original peptide. The optimized peptide StAMP-9 displayed bactericidal activity, with minimal inhibitory concentrations of 7.8 µg/mL against Staphylococcus aureus and 3.9 µg/mL against Escherichia coli, and no cytotoxic effects against mammalian cells. Preliminary experiments indicate the bacterial membranes as immediate and primary targets.</jats:p