Structural Determinants of Antimicrobial and Antiplasmodial Activity and Selectivity in Histidine-rich Amphipathic Cationic Peptides

Designed histidine-rich amphipathic cationic peptides, such as LAH4, have enhanced membrane disruption and antibiotic properties when the peptide adopts an alignment parallel to the membrane surface. Although this was previously achieved by lowering the pH, here we have designed a new generation of...

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Published in:	The Journal of biological chemistry Vol. 284; no. 1; pp. 119 - 133
Main Authors:	Mason, A. James, Moussaoui, Wardi, Abdelrahman, Tamer, Boukhari, Alyae, Bertani, Philippe, Marquette, Arnaud, Shooshtarizaheh, Peiman, Moulay, Gilles, Boehm, Nelly, Guerold, Bernard, Sawers, Ruairidh J.H., Kichler, Antoine, Metz-Boutigue, Marie-Háléne, Candolfi, Ermanno, Právost, Gilles, Bechinger, Burkhard
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 02-01-2009 American Society for Biochemistry and Molecular Biology
Subjects:	Anti-Infective Agents - chemistry Antimalarials - chemistry Antimicrobial Cationic Peptides - chemistry Cell Membrane - chemistry Chemical Sciences Histidine - chemistry Hydrogen-Ion Concentration Hydrophobic and Hydrophilic Interactions Medicinal Chemistry Peptides - chemistry Protein Structure, Secondary Structure-Activity Relationship
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Summary:	Designed histidine-rich amphipathic cationic peptides, such as LAH4, have enhanced membrane disruption and antibiotic properties when the peptide adopts an alignment parallel to the membrane surface. Although this was previously achieved by lowering the pH, here we have designed a new generation of histidine-rich peptides that adopt a surface alignment at neutral pH. In vitro, this new generation of peptides are powerful antibiotics in terms of the concentrations required for antibiotic activity; the spectrum of target bacteria, fungi, and parasites; and the speed with which they kill. Further modifications to the peptides, including the addition of more hydrophobic residues at the N terminus, the inclusion of a helix-breaking proline residue or using d-amino acids as building blocks, modulated the biophysical properties of the peptides and led to substantial changes in toxicity to human and parasite cells but had only a minimal effect on the antibacterial and antifungal activity. Using a range of biophysical methods, in particular solid-state NMR, we show that the peptides are highly efficient at disrupting the anionic lipid component of model membranes. However, we also show that effective pore formation in such model membranes may be related to, but is not essential for, high antimicrobial activity by cationic amphipathic helical peptides. The information in this study comprises a new layer of detail in the understanding of the action of cationic helical antimicrobial peptides and shows that rational design is capable of producing potentially therapeutic membrane active peptides with properties tailored to their function.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0021-9258 1083-351X
DOI:	10.1074/jbc.M806201200