期刊
JOURNAL OF COLLOID AND INTERFACE SCIENCE
卷 533, 期 -, 页码 492-502出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.jcis.2018.08.042
关键词
Antimicrobial peptide; Salt resistance; Non-natural amino acid; Lipopolysaccharide (LPS) neutralization
资金
- Ministry of Science and Technology, Taiwan [106-2113-M-007-005]
- National Taiwan Hospital, Hsinchu Branch
- Resource Center, National Research Program for Biopharmaceuticals, Taiwan [SB3, NSC-100-2325-B-080-001]
Hypothesis Release of lipopolysaccharides (LPS) from bacteria into bloodstream may cause serious unwanted stimulation of the host immune system. P-113 is a clinically active histidine-rich antimicrobial peptide. Nal-P-113, a beta-naphthylalanine-substituted P-113, is salt-resistant but has limited LPS neutralizing activity. We suspected the size and shape of the non-natural bulky amino acid may affect its LPS neutralizing activity. Herein, antimicrobial, LPS neutralizing, and antiproteolytic effects of phenylalanine- (Phe-P-113), beta-naphthylalanine- (Nal-P-113), beta-diphenylalanine- (Dip-P-113), and beta-(4,4'-biphenyl)alanine- (Bip-P-113) substituted P-113 were studied. Experiments Structure-activity relationships of P-113, Phe-P-113, Nal-P-113, Dip-P-113, and Bip-P-113 were evaluated using antimicrobial activity assays, serum proteolytic assays, peptide-induced permeabilization of large unilamellar vesicles, zeta potential measurements, dynamic light scattering measurement of LPS aggregation, and Limulus amebocyte lysate assays for measuring LPS neutralization. In vitro and in vivo LPS neutralizing activities were further confirmed by LPS-induced inflammation inhibition in an endotoxemia mouse model. Findings Bip-P-113 and Dip-P-113 had the longest and widest non-nature amino acids, respectively. Bip-P-113 enhanced salt resistance, serum proteolytic stability, peptide-induced permeabilization, zeta potential measurements, LPS aggregation, and in vitro and in vivo LPS neutralizing activities. These results could help design novel antimicrobial peptides that have enhanced stability in vivo and that can have potential therapeutic applications. (C) 2018 Elsevier Inc. All rights reserved.
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