Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 64, Issue 20, Pages 15349-15366Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.1c01352
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Funding
- CSIR [CII7037, MLP107]
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By designing novel antimicrobial peptides based on the sequence of the human host defense protein chemerin, researchers identified a seven-residue amphipathic stretch with high density of hydrophobic and positively charged residues. A 14-residue tandem repeat derived from this stretch showed high activity against various bacteria and potential for use in combating infections.
To design novel antimicrobial peptides by utilizing the sequence of the human host defense protein, chemerin, a seven-residue amphipathic stretch located in the amino acid region, 109-115, was identified, which possesses the highest density of hydrophobic and positively charged residues. Although this 7-mer peptide was inactive toward microorganisms, its 14-mer tandem repeat (Chem-KVL) was highly active against different bacteria including methicillin-resistant Staphylococcus aureus, a multidrug-resistant Staphylococcus aureus strain, and slow- and fast-growing mycobacterial species. The selective enantiomeric substitutions of its two L-lysine residues were attempted to confer cell selectivity and proteolytic stability to Chem-KVL. Chem-8dK with a D-lysine replacement in its middle (eighth position) showed the lowest hemolytic activity against human red blood cells among Chem-KVL analogues and maintained high antimicrobial properties. Chem-8dK showed in vivo efficacy against Pseudomonas aeruginosa infection in BALB/c mice and inhibited the development of resistance in this microorganism up to 30 serial passages and growth of intracellular mycobacteria in THP-1 cells.
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