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Abstract
Drug-resistant Gram-negative bacterial pathogens and endotoxin- or lipopolysaccharide (LPS)-mediated inflammations are among some of the most prominent health issues globally. Antimicrobial peptides (AMPs) are eminent molecules that can kill drug-resistant strains and neutralize LPS toxicity. LPS, the outer layer of the outer membrane of Gram-negative bacteria safeguards cell integrity against hydrophobic compounds, including antibiotics and AMPs. Apart from maintaining structural integrity, LPS, when released into the blood stream, also induces inflammatory pathways leading to septic shock. In previous works, we have reported the de novo design of a set of 12-amino acid long cationic/hydrophobic peptides for LPS binding and activity. These peptides adopt β-boomerang like conformations in complex with LPS. Structure-activity studies demonstrated some critical features of the β-boomerang scaffold that may be utilized for the further development of potent analogs. In this work, β-boomerang lipopeptides were designed and structure-activity correlation studies were carried out. These lipopeptides were homo-dimerized through a disulfide bridge to stabilize conformations and for improved activity. The designed peptides exhibited potent antibacterial activity and efficiently neutralized LPS toxicity under in vitro assays. NMR structure of C4YI13C in aqueous solution demonstrated the conserved folding of the lipopeptide with a boomerang aromatic lock stabilized with disulfide bond at the C-terminus and acylation at the N-terminus. These lipo-peptides displaying bacterial sterilization and low hemolytic activity may be useful for future applications as antimicrobial and antiendotoxin molecules.
Highlights
Development of novel antimicrobial peptides (AMPs) is urgently needed to combat against rapidly appearing drug resistant strains [1,2,3]
AMPs may be categorized based on their structures namely (a) α-helix, (b) β-sheet or β-hairpin stabilized by disulfide bridges, (c) extended and (d) loops with or without disulfide bonds
LPS or endotoxin induces inflammatory pathways leading to the production of cytokines that often results in septic shock [19,20,21]
Summary
Development of novel antimicrobial peptides (AMPs) is urgently needed to combat against rapidly appearing drug resistant strains [1,2,3]. We have utilized the most active analog of the second generation of β-boomerang peptide, YI12WF (YVLWKRKRFIFIamide) as a starting template for further design of potent antimicrobial activity and LPS neutralization peptide analogs. Toward this end, we have prepared analogs of YI12WF containing five basic residues (YVLWKRKRKFCFI-amide) in the loop of the β-boomerang structure and which are acylated at the. Biophysical studies, using optical spectroscopic methods, ITC and dynamic light scattering have provided molecular insights into the mode of action of the designed peptides in Gram-negative bacterial outer membrane and endotoxin neutralization. These β-boomerang lipopeptides may be used in developing non-toxic antibacterial therapeutics
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