Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 68, Issue -, Pages 10-18Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2013.07.008
Keywords
Histidine-derived amino acid; Antimicrobial peptidomimetics; Salt resistance; Anti-MRSA activity; Protease stability
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Funding
- Korea Basic Science Institute's research grant [T33418, T33518]
- National Cancer Institute's Intramural Research grant
- Korea Research Foundation
- Korean Government [KRF-2011-0009039]
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Here we report for the first time the synthesis of Histidine (His) derived lipo-amino acids having pendant lipid tails at N(tau)- and N(pi)-positions on imidazole group of His and applied it into synthesis of lipo-peptides. The attachment of His-derived lipo-amino acid into the very short inactive cationic peptides endows potent antimicrobial activity against Gram-positive and Gram-negative bacteria without hemolytic activity. Furthermore, our designed His-derived lipo-peptidomimetics (HDLPs) consisting of two or three residues displayed strong anti-MRSA activity and protease stability as well as retained potent antimicrobial activity under high salt concentration. Our results demonstrate that the novel lipo-amino acid is highly flexible to synthesize and carry out the extensive structure activity relationship (SAR) on lipo-antimicrobial peptidomimetics and represents a unique amenable platform for modifying parameters important for antimicrobial activity. Through this study, we proved that the discovery of His-derived lipo-amino acid and the corresponding HDLPs are an excellent candidate as a lead compound for the development of novel antimicrobial agents. (C) 2013 Elsevier Masson SAS. All rights reserved.
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