A novel method, based on the rational and systematic modulation of macroscopic structural characteristics on a template originating from a large number of natural, cell-lytic, amphipathic α-helical peptides, was used to probe how the depths and shapes of hydrophobic and polar faces and the conformational stability affect antimicrobial activity and selectivity with respect to eukaryotic cells. A plausible mode of action explaining the peptides' behaviour in model membranes, bacteria and host cells is proposed. Cytotoxic activity, in general, correlated strongly with the hydrophobic sector depth, and required a majority of aliphatic residue side chains having more than two carbon atoms. It also correlated significantly with the size of polar sector residues, which determines the penetration depth of the peptide via the so-called snorkel effect. Both an oblique gradient of long to short aliphatic residues along the hydrophobic face and a stabilized helical structure increased activity against host cells but not against bacteria, as revealed by haemolysis, flow cytofluorimetric studies on lymphocytes and surface plasmon resonance studies with model phosphatidylcholine/cholesterol membranes. The mode of interaction changes radically for a peptide with a stable, preformed helical conformation compared with others that form a structure only on membrane binding. The close correlation between effects observed in biological and model systems suggests that the ‘carpet model’ correctly represents the type of peptides that are bacteria-selective, whereas the behaviour of those that lyse host cells is more complex.
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Research Article|
August 09 2005
Controlled alteration of the shape and conformational stability of α-helical cell-lytic peptides: effect on mode of action and cell specificity
Igor Zelezetsky;
Igor Zelezetsky
*Department of Biochemistry, Biophysics and Macromolecular Chemistry, University of Trieste, I-34127 Trieste, Italy
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Sabrina Pacor;
Sabrina Pacor
†Department of Biomedical Sciences, University of Trieste, I-34127 Trieste, Italy
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Ulrike Pag;
Ulrike Pag
‡Institute for Medical Microbiology and Immunology, University of Bonn, 53105 Bonn, Germany
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Niv Papo;
Niv Papo
§Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel
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Yechiel Shai;
Yechiel Shai
§Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel
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Hans-Georg Sahl;
Hans-Georg Sahl
‡Institute for Medical Microbiology and Immunology, University of Bonn, 53105 Bonn, Germany
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Alessandro Tossi
Alessandro Tossi
1
*Department of Biochemistry, Biophysics and Macromolecular Chemistry, University of Trieste, I-34127 Trieste, Italy
1To whom correspondence should be addressed (email tossi@bbcm.units.it).
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Publisher: Portland Press Ltd
Received:
December 23 2004
Revision Received:
April 05 2005
Accepted:
April 19 2005
Accepted Manuscript online:
April 19 2005
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London
2005
Biochem J (2005) 390 (1): 177–188.
Article history
Received:
December 23 2004
Revision Received:
April 05 2005
Accepted:
April 19 2005
Accepted Manuscript online:
April 19 2005
Citation
Igor Zelezetsky, Sabrina Pacor, Ulrike Pag, Niv Papo, Yechiel Shai, Hans-Georg Sahl, Alessandro Tossi; Controlled alteration of the shape and conformational stability of α-helical cell-lytic peptides: effect on mode of action and cell specificity. Biochem J 15 August 2005; 390 (1): 177–188. doi: https://doi.org/10.1042/BJ20042138
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