Artificial β-defensin based on a minimal defensin template
Résumé
We have designed and chemically synthesised an artificial β-defensin based on a minimal template derived from the comparative analysis of over 80 naturally occurring sequences. This molecule has the disulfide-bridged, β-sheet core structure of natural β-defensins and shows a robust, salt-sensitive antimicrobial activity against bacteria and yeast, as well as a chemotactic activity against immature dendritic cells. An SAR study using two truncated fragments or a Cys→Ser point-mutated analogue, in which one or two of the three disulphide bridges were absent, indicated that altering the structure resulted in a different type of membrane interaction and a switch to different modes of action towards both microbial and host cells, and that covalent dimerisation could favour antimicrobial activity. Comparison of the structural, aggregational and biological activities of the artificial defensin with those of three human β-defensins and their primate orthologues provided useful information on how their mode of action may relate to specific structural features.
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