Structural correlates of antimicrobial efficacy in IL-8 and related human kinocidins |
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Authors: | Nannette Y Yount Alan J Waring Kimberly D Gank William H Welch Michael R Yeaman |
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Institution: | a Division of Infectious Diseases, LAC-Harbor UCLA Medical Center, Torrance, CA 90509, USA b St. John’s Cardiovascular Research Center, Torrance, CA 90502, USA c Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90024, USA d Department of Biochemistry, University of Nevada, Reno, NV 89557, USA |
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Abstract: | Chemokines are small (8-12 kDa) effector proteins that potentiate leukocyte chemonavigation. Beyond this role, certain chemokines have direct antimicrobial activity against human pathogenic organisms; such molecules are termed kinocidins. The current investigation was designed to explore the structure-activity basis for direct microbicidal activity of kinocidins. Amino acid sequence and 3-dimensional analyses demonstrated these molecules to contain iterations of the conserved γ-core motif found in broad classes of classical antimicrobial peptides. Representative CXC, CC and C cysteine-motif-group kinocidins were tested for antimicrobial activity versus human pathogenic bacteria and fungi. Results demonstrate that these molecules exert direct antimicrobial activity in vitro, including antibacterial activity of native IL-8 and MCP-1, and microbicidal activity of native IL-8. To define molecular determinants governing its antimicrobial activities, the IL-8 γ-core (IL-8γ) and α-helical (IL-8α) motifs were compared to native IL-8 for antimicrobial efficacy in vitro. Microbicidal activity recapitulating that of native IL-8 localized to the autonomous IL-8α motif in vitro, and demonstrated durable microbicidal activity in human blood and blood matrices ex vivo. These results offer new insights into the modular architecture, context-related deployment and function, and evolution of host defense molecules containing γ-core motifs and microbicidal helices associated with antimicrobial activity. |
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Keywords: | PF-4 platelet factor 4 PMP platelet microbicidal protein PBP platelet basic protein CTAP-3 connective tissue-activating peptide 3 β-TG beta thromboglobulin NAP-2 neutrophil activating peptide-2 RANTES releasable upon activation normal T cell expressed and secreted CXC cysteine-X-cysteine CC cysteine-cysteine CXCR CXC receptor CCR CC receptor YNB yeast nitrogen broth QSAR quantitative structure-activity relationship CD circular dichroism F-moc (9-fluorenyl-methyloxycarbonyl) TFA trifluoroacetic acid MALDI-TOF matrix-assisted laser desorption ionization time-of-flight PIPES piperazine-N N&prime -bis[2-ethanesulfonic acid] Da daltons and standard single letter codes for amino acids |
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