Human neutrophil defensins, and their analogues incorporating anionic, hydrophobic or cationic residues at the N- and C-termini, were synthesized by solid-phase procedures. The synthetic defensins were examined for their microbicidal activity against Candida albicans, two Gram-negative bacteria (Actinobacillus actinomycetemcomitans and Porphyromonas gingivalis) and two Gram-positive bacteria (Streptococcus gordonii and Streptococcus mutans). The human neutrophil peptide 1 (HNP1) and HNP2 were found to be potent candidacidal agents. HNP3, which differs by one amino acid at the N-terminus of its sequence, was totally inactive. The Gram-negative bacteria A. actinomycetemcomitans and P. gingivalis and the Gram-positive bacteria S. gordonii and S. mutans were insensitive to human defensins. However, the insertion of two basic residues, such as arginine, at both the N-terminus and the C-terminus of HNP2 significantly enhanced antifungal and antibacterial activity. The addition of anionic residues, such as aspartic acid, at the N- and C-termini rendered the molecule totally inactive. The presence of two hydrophobic amino acids, such as valine, at the N-terminus of HNP2 and of two basic arginine residues at its C-terminus resulted in molecules that were optimally active against these oral pathogens. The results suggest that the N- and C-terminal residues in defensin peptides are the crucial functional elements that determine their microbicidal potency. The three-dimensional structure of all defensins constitutes the same amphiphilic β-sheet structure, with the polar face formed by the N- and C-terminal residues playing an important role in defining microbicidal potency and the antimicrobial spectrum. The enhanced microbicidal activity observed for defensin peptides with two basic residues at both the N- and C-termini could be due to optimization of the amphiphilicity of the structure, which could facilitate specific interactions with the microbial membranes.
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Research Article|
April 25 2000
Large-scale synthesis and functional elements for the antimicrobial activity of defensins
Periathamby Antony RAJ;
Periathamby Antony RAJ
1
*Division of Periodontics, School of Dentistry, Marquette University, 570 North 16th Street, Milwaukee, WI 53201, U.S.A.
†Department of Oral Biology and Periodontal Disease Research Center, State University of New York at Buffalo, 311 Foster Hall, 3435 Main Street, Buffalo, NY 14214, U.S.A.
1To whom correspondence should be addressed, at School of Dentistry, Marquette University (e-mail Periathambya@;vms.csd.mu.edu).
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Kavitha J. ANTONYRAJ;
Kavitha J. ANTONYRAJ
†Department of Oral Biology and Periodontal Disease Research Center, State University of New York at Buffalo, 311 Foster Hall, 3435 Main Street, Buffalo, NY 14214, U.S.A.
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Thonthi KARUNAKARAN
Thonthi KARUNAKARAN
†Department of Oral Biology and Periodontal Disease Research Center, State University of New York at Buffalo, 311 Foster Hall, 3435 Main Street, Buffalo, NY 14214, U.S.A.
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Publisher: Portland Press Ltd
Received:
November 15 1999
Revision Received:
January 24 2000
Accepted:
February 22 2000
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London © 2000
2000
Biochem J (2000) 347 (3): 633–641.
Article history
Received:
November 15 1999
Revision Received:
January 24 2000
Accepted:
February 22 2000
Citation
Periathamby Antony RAJ, Kavitha J. ANTONYRAJ, Thonthi KARUNAKARAN; Large-scale synthesis and functional elements for the antimicrobial activity of defensins. Biochem J 1 May 2000; 347 (3): 633–641. doi: https://doi.org/10.1042/bj3470633
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