We have designed and chemically synthesized 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 (structure–activity relationship) study using two truncated
fragments or a Cys→Ser point-mutated analogue, from which
one or two of the three disulfide 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 dimerization
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.
