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Melectin MAPs: the influence of dendrimerization on antimicrobial and hemolytic activity
Petr Niederhafner1, Lucie Bednárová, Miloš Buděšínský
1Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo nám. 2, 166 10, Prague 6, Czech Republic.
Abstract:
The recently described antimicrobial peptide melectin (MEP, GFLSILKKVLPKVMAHMK-NH2) exhibits high antimicrobial activity against Gram-positive and Gram-negative bacteria. Here we describe the synthesis and biological activities of 23 new analogues of MEP. We studied the influence of dimerization and tetramerization (MAP-constructs of MEP) on the antimicrobial and hemolytic activities, as well as the role of Met in positions 14 and 17 of the peptide chain. Oxidation of the Met to Met(O) and Met(O2) decreases antimicrobial activity of all tested bacteria if the peptide is in the monomeric form, however, only to Staphylococcus aureus if in the form of dimer or tetramer. Dimerization and tetramerization increase the undesirable hemolytic activity of the peptides. Interestingly, substitution of Leu for Val in position 6 leads to the decrease of hemolytic activity. Introduction of the isosteric amino acid Nle into positions 14 or 17 or both leads to slight increase of hemolytic activity under preservation of high antimicrobial activities. Unfortunately, dimerization again leads to an increase of hemolytic activity.
Insights
Researchers synthesized 23 melectin analogues to enhance antimicrobial activity. Dimerization and tetramerization boosted antimicrobial effects but also increased hemolytic activity, while specific amino acid substitutions modulated these properties.
Area of Science:
- Biochemistry
- Medicinal Chemistry
- Microbiology
Background:
- Melectin (MEP) is a recently discovered antimicrobial peptide with broad-spectrum activity.
- Antimicrobial peptides are crucial in combating bacterial infections, necessitating the development of novel analogues.
Purpose of the Study:
- To synthesize and evaluate 23 novel melectin analogues.
- To investigate the impact of dimerization, tetramerization, and specific amino acid modifications on MEP's antimicrobial and hemolytic activities.
Main Methods:
- Peptide synthesis of melectin analogues.
- Antimicrobial activity assays against Gram-positive and Gram-negative bacteria.
- Hemolytic activity assays.
- Analysis of methionine oxidation and amino acid substitutions (Leu to Val, Met to Nle).
Main Results:
- Dimerization and tetramerization of MEP enhanced antimicrobial activity but also increased hemolytic activity.
- Methionine oxidation reduced antimicrobial activity in monomeric MEP but had a lesser effect on dimeric/tetrameric forms against S. aureus.
- Substitution of Leu6 with Val decreased hemolytic activity, while Nle substitutions at positions 14/17 slightly increased hemolytic activity while maintaining antimicrobial potency.
Conclusions:
- Peptide multimerization (dimerization/tetramerization) is a viable strategy to enhance MEP's antimicrobial efficacy.
- Careful amino acid substitution and modification are necessary to balance antimicrobial activity with reduced hemolytic toxicity.
- Further optimization of melectin analogues is warranted for therapeutic development.
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