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Linear Analogues of Human β‐Defensin 3: Concepts for Design of Antimicrobial Peptides with Reduced Cytotoxicity to Mammalian Cells
Author(s) -
Liu Shouping,
Zhou Lei,
Li Jing,
Suresh Anita,
Verma Chandra,
Foo Yong Hwee,
Yap Eric P. H.,
Tan Donald T. H.,
Beuerman Roger W.
Publication year - 2008
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.200700560
Subject(s) - cytotoxicity , defensin , hemolysis , beta defensin , antimicrobial , circular dichroism , chemistry , antimicrobial peptides , structure–activity relationship , peptide , biochemistry , in vitro , biology , immunology , organic chemistry
A series of engineered linear analogues [coded as F6, W6, Y6, A6, S6 and C(Acm)6] were modeled, designed, synthesized and structurally characterized by mass spectra, circular dichroism, hydrophobicity analysis and molecular modeling. We have screened antimicrobial activity, hemolysis to rabbit erythrocytes, and cytotoxicity to human conjunctival epithelial cells. No significant hemolytic effect was observed for hBD3 or from five of the six analogues [F6, Y6, A6, S6 and C(Acm)6] over the range of 3–100 μg mL −1 . The six linear analogues have reduced cytotoxicity to human conjunctival epithelial cells over the range of 6–100 μg mL −1 compared to hBD3. By tuning the overall hydrophobicity of linear hBD3 analogues, reduced cytotoxicity and hemolysis were obtained while preserving the antimicrobial properties. The decreased cytotoxicity of the linear analogues is suggested to be structurally related to the removal of disulfide bridges, and the flexible structure of the linear forms, which seem to be associated with loss of secondary structure. These results suggest a new approach for guiding the design of new linear analogues of defensin peptides with strong antibiotic properties and reduced cytotoxicity to mammalian cells.