Journal
JOURNAL OF INNATE IMMUNITY
Volume 1, Issue 3, Pages 268-280Publisher
KARGER
DOI: 10.1159/000174822
Keywords
Host defense peptide; Antimicrobial peptides; Cathelicidins; Innate immunity; Structure-activity relationship; Endotoxin; Antibiotic resistance
Categories
Funding
- NIH [S10-RR022392]
- NSF [MCB0236039, EPS0236913]
- USDA CSREES [2008-35204-04544]
- Kansas State University COBRE and Targeted Excellence Programs
- Oklahoma Center for the Advancement of Science and Technology [HR03-146, HR07-113, AR07.2-087]
- Oklahoma Agricultural Experiment Station [H-2507]
- NATIONAL CENTER FOR RESEARCH RESOURCES [S10RR022392] Funding Source: NIH RePORTER
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Fowlicidins are a group of newly identified chicken cathelicidin host defense peptides. We have shown that the putatively mature fowlicidin-2 of 31 amino acid residues possesses potent antibacterial and lipopolysaccharide (LPS)neutralizing activities, but with a noticeable toxicity to mammalian cells. As a first step in exploring the structure-activity relationships of fowlicidin-2, in this study we determined its tertiary structure by nuclear magnetic resonance spectroscopy. Unlike the majority of cathelicidins, which are composed of a predominant alpha-helix with a short hinge sequence near the center, fowlicidin-2 consists of 2 well-defined a-helical segments (residues 6-12 and 23-27) connected by a long extensive kink (residues 13-20) induced by proline. To further investigate the functional significance of each of these structural components, several N- and C-terminal deletion analogs of fowlicidin-2 were synthesized and analyzed for their antibacterial, cytotoxic and LPS-neutralizing activities. Our results indicated that neither the N- nor C-terminal alpha-helix alone is sufficient to confer any function. Rather, fowlicidin-2(1-18) and fowlicidin-2(15-31), 2 alpha-helical segments with inclusion of the central cationic kink region, retained substantial capacities to kill bacteria and neutralize the LPS-induced proinflammatory response, relative to the parent peptide. More desirably, these 2 peptide analogs showed substantially reduced toxicity to human erythrocytes and epithelial cells, indicative of improved potential as antibacterial and antisepsis agents. To our knowledge, fowlicidin-2 is the first a-helical cathelicidin, with the central kink region shown to be critically important in killing bacteria and neutralizing LIPS. Copyright (C) 2008 S. Karger AG, Basel
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