Antimicrobial peptides (AMPs) have attracted great attention
as
next generation antibiotics for the treatment of multidrug-resistant
(MDR) bacterial infections. Poor proteolytic stability has however
undermined clinical applications of AMPs. A novel peptide cyclization
approach is described to enhance the in vivo antibacterial
activity of AMPs. Bicyclic antimicrobial peptides were synthesized
by cross-linking the ε-amino groups of three lysine residues
with a 1,3,5-trimethylene benzene spacer. In a proof of principal
study, four bicyclic peptides were synthesized from the cationic AMP
OH-CM6. One bicyclic peptide retained strong antimicrobial activity
and low toxicity but exhibited a prolonged half-life in serum. Antibacterial
activity was consequently improved in vivo without
renal or hepato-toxicity. The novel peptide cyclization approach represents
an important tool for enhancing AMP proteolytic stability for improved
treatment of bacterial infection.
Cationic
antimicrobial peptides (CAMPs) are promising for treatment
of multidrug-resistant (MDR) bacteria-caused infections. However,
clinical application of CAMPs has been hampered mostly due to their
poor proteolytic stability and hemolytic toxicity. Recently, lysine-stapled
CAMPs developed by us had been proved to increase peptide stability in vitro without induction of hemolysis. Herein, the applicability
of the lysine stapling strategy was further explored by using five
natural or artificial CAMPs as model peptides. Lysine stapling screening
was implemented to provide 13 cyclic analogues in total. Biological
screening of these cyclic analogues showed that CAMPs with a better
amphiphilic structure were inclined to exhibit improved antimicrobial
activity, protease stability, and biocompatibility after lysine-stapling.
One of the stapled analogues of BF15-a1 was found to have extended
half-life in plasma, enhanced antimicrobial activity against clinically
isolated MDR ESKAPE pathogens, and remained highly effective in combating
MRSA infection in a mouse model.
Antimicrobial peptides (AMPs) have great potentials for developing novel antibiotics against multi‐drug resistant (MDR) bacteria. However, the clinical application of AMPs is limited due to their poor protease stability and high hemolytic toxicity. Various strategies have been widely explored to improve the pharmacological properties of natural or artificial antimicrobial peptides, including D‐ or non‐natural amino acid residue replacement, backbone modification, cyclization, PEGlytion, and lipidation. Among others, peptide cyclization, which has been widely applied to enhance the biostability and target selectivity of bioactive peptide, is a very appealing and promising strategy for developing novel antibiotics based on AMPs. Herein, we summarize the current strategies for synthesizing cyclic antimicrobial peptides and the resulting influence of peptide cyclization on the biological activities.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.