Lysine Nε-Trimethylation, a Tool for Improving the Selectivity of Antimicrobial Peptides
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- 作者：Mara Fernndez-Reyes ; Dolores Daz ; Beatriz G. de la Torre ; Ania Cabrales-Rico ; Mariona Valls-Miret ; Jess Jimnez-Barbero ; David Andreu ; Luis Rivas
- 刊名：Journal of Medicinal Chemistry
- 出版年：2010
- 出版时间：August 12, 2010
- 年：2010
- 卷：53
- 期：15
- 页码：5587-5596
- 全文大小：957K
- 年卷期：v.53,no.15(August 12, 2010)
- ISSN：1520-4804
文摘
The effects of lysine Nε-trimethylation at selected positions of the antimicrobial cecropin A−melittin hybrid peptide KWKLFKKIGAVLKVL-amide have been studied. All five monotrimethylated, four bis-trimethylated plus the per-trimethylated analogues have been synthesized and tested for antimicrobial activity on Leishmania parasites and on Gram-positive and -negative bacteria, as well as for hemolysis of sheep erythrocytes as a measure of cytotoxicity. The impact of trimethylation on the solution conformation of selected analogues has been evaluated by NMR, which indicates a slight decrease in the α-helical content of the modified peptides, particularly in the N-terminal region. Trimethylation also enhances the proteolytic stability of mono- and bis-trimethylated analogues by 2−3-fold. Although it tends to lower antimicrobial activity in absolute terms, trimethylation causes an even higher decrease in hemolytic activity and therefore results in improved selectivity for several analogues. The monotrimethylated analogue at position 6 shows the overall best selectivity against both the Leishmania donovani protozoan and Acinetobacter baumannii, a Gram-negative bacterium of increasing clinical concern.