Piscidin-1-analogs with double L- and D-lysine residues exhibited different conformations in lipopolysaccharide but comparable anti-endotoxin activities

To become clinically effective, antimicrobial peptides (AMPs) should be non-cytotoxic to host cells. Piscidins are a group of fish-derived AMPs with potent antimicrobial and antiendotoxin activities but limited by extreme cytotoxicity. We conjectured that introduction of cationic residue(s) at the i...

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Published in:Scientific reports 2017-01, Vol.7 (1), p.39925-39925, Article 39925
Main Authors: Kumar, Amit, Mahajan, Mukesh, Awasthi, Bhanupriya, Tandon, Anshika, Harioudh, Munesh Kumar, Shree, Sonal, Singh, Pratiksha, Shukla, Praveen Kumar, Ramachandran, Ravishankar, Mitra, Kalyan, Bhattacharjya, Surajit, Ghosh, Jimut Kanti
Format: Article
Language:English
Subjects:
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Antibacterial activity
Antimicrobial peptides
Cytotoxicity
Endotoxins
Helix-loop-helix
Humanities and Social Sciences
Hydrophobicity
Inflammation
Lipid A
Lipopolysaccharides
Lysine
multidisciplinary
Peptides
Residues
Science
Threonine
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Summary:To become clinically effective, antimicrobial peptides (AMPs) should be non-cytotoxic to host cells. Piscidins are a group of fish-derived AMPs with potent antimicrobial and antiendotoxin activities but limited by extreme cytotoxicity. We conjectured that introduction of cationic residue(s) at the interface of polar and non-polar faces of piscidins may control their insertion into hydrophobic mammalian cell membrane and thereby reducing cytotoxicity. We have designed several novel analogs of piscidin-1 by substituting threonine residue(s) with L and D-lysine residue(s). L/D-lysine-substituted analogs showed significantly reduced cytotoxicity but exhibited either higher or comparable antibacterial activity akin to piscidin-1. Piscidin-1-analogs demonstrated higher efficacy than piscidin-1 in inhibiting lipopolysaccharide (LPS)-induced pro-inflammatory responses in THP-1 cells. T15,21K-piscidin-1 (0.5 mg/Kg) and T15,21dK-piscidin-1 (1.0 mg/Kg) demonstrated 100% survival of LPS (12.0 mg/Kg)-administered mice. High resolution NMR studies revealed that both piscidin-1 and T15,21K-piscidin-1 adopted helical structures, with latter showing a shorter helix, higher amphipathicity and cationic residues placed at optimal distances to form ionic/hydrogen bond with lipid A of LPS. Remarkably, T15,21dK-piscidin-1 showed a helix-loop-helix structure in LPS and its interactions with LPS could be sustained by the distance of separation of side chains of R7 and D-Lys-15 which is close to the inter-phosphate distance of lipid A.
ISSN:2045-2322
2045-2322
DOI:10.1038/srep39925