Antimicrobial
peptides are an integral part of innate immunity. Sequences
of antimicrobial peptides generally include a mixture of cationic
and hydrophobic residues. Some antimicrobial peptides adopt
amphiphilic alpha-helical structures in the presence of a membrane
bilayer; others form beta-sheet or beta-hairpin structures.
All antimicrobial peptides are thought to function by permeabilizing
the bacterial membrane.
We have
designed a variety of peptides with antimicrobial activity using
both natural and unnatural scaffolds. The beta peptides were
designed to form amphiphilic helices upon folding, while the
side chains in the beta-sheet form a hydrophobic core flanked
by regions of positive charge.
Designs for antimicrobial peptides. Clockwise
from top left: (1) an amphiphilic 12-helical beta-peptide;
(2) an amphiphilic 14-helical beta peptide; (3) a beta sheet
with hydrophobic and cationic groups.
Antimicrobial
Beta-Peptides
We
have designed a series of 12- and 14-helical beta peptides with
antimicrobial activity. These peptides form amphiphilic helices
in water, similar to the natural antimicrobial agent magainin.
Some of these antimicrobial agents can be seen below. The image
on the left shows a series of 12-helical peptides composed of
our five membered ring residues, ACPC and APC. The image on
the right shows a series of 14-helical peptides composed of
acyclic and six-membered ring ACHC residues.
Antimicrobial
Beta-Sheets
Protegrins
are antimicrobial peptides from porcine leukocytes that have
therapeutic potential as a treatment for Cystic Fibrosis. Protegrin-1
is a highly cationic 18-mer that adopts a beta-hairpin structure
in solution that is stabilized by two disulfide bonds. Previous
studies have shown that these disulfide bonds are essential
for antimicrobial activity. Using molecular design, we have
generated Protegrin-1 analogues that lack cysteine but nevertheless
display potent antibacterial activity.
