Swapping Lysine for Ornithine Makes Stapled Antimicrobial Peptides More Potent and Stable | Research

The takeaway

Substituting lysine with ornithine in stapled cationic antimicrobial heptapeptides enhanced antimicrobial activity and proteolytic stability while maintaining low hemolytic activity.

Ornithine > Lysine
substitution enhanced antimicrobial activity and proteolytic stability in stapled AMPs

What the researchers found

Ornithine substitution for lysine in stapled heptapeptide AMPs enhanced antimicrobial activity and proteolytic stability while maintaining low hemolytic activity.

Why it matters

Antimicrobial resistance is a growing global crisis. Developing more potent and stable antimicrobial peptides through simple amino acid substitutions could accelerate the pipeline of new antibiotics.

The numbers in context

7-amino-acid peptides (heptapeptides) with all-hydrocarbon staples; various lysine homologues tested.

How the study worked

Structure-activity study testing lysine-homologue substitutions (ornithine, diaminobutyric acid, diaminopropionic acid) in hydrocarbon-stapled cationic heptapeptides, assessing helicity, antimicrobial MICs, hemolytic activity, and proteolytic stability.

Who was studied

Synthetic stapled heptapeptides tested against bacteria

What this study cannot tell us

In vitro antimicrobial testing only; no in vivo efficacy or toxicity data; limited peptide length (7 residues); mechanism of enhanced activity not fully elucidated; narrow range of bacterial species tested.

How to read the evidence

Preliminary in vitro evidence demonstrating a clear structure-activity relationship. Well-characterized but lacking in vivo validation.

When this study was published

Published in 2024, contributing practical optimization strategies to the antimicrobial peptide field.

The bigger picture

The combination of peptide stapling with lysine-homologue optimization represents a dual strategy for improving antimicrobial peptides — stapling provides structural stability while ornithine substitution enhances both activity and enzyme resistance.

Questions still open

Does ornithine substitution similarly enhance longer antimicrobial peptides?
What is the mechanism by which the shorter ornithine side chain improves antimicrobial activity?
Can this optimization strategy be combined with other modifications for further improvement?

Common questions

What is ornithine and why does it help antimicrobial peptides?

Ornithine is a natural amino acid similar to lysine but with a slightly shorter side chain. When it replaces lysine in antimicrobial peptides, it somehow makes them better at killing bacteria and more resistant to breakdown by enzymes, while staying safe for human cells.

Could this lead to new antibiotics?

It's a promising optimization strategy. By combining peptide stapling (for structural stability) with ornithine substitution (for better activity and enzyme resistance), researchers can create more effective antimicrobial peptide drug candidates.

Read the original research

Lysine-homologue substitution: Impact on antimicrobial activity and proteolytic stability of cationic stapled heptapeptides.

Bioorganic & medicinal chemistry, 106, 117735

View on PubMed ↗Publisher’s paper ↗

Citation

Tran, Duc V H; Luong, Huy X; Kim, Do-Hee; Lee, Bong-Jin; Kim, Young-Woo. (2024). Lysine-homologue substitution: Impact on antimicrobial activity and proteolytic stability of cationic stapled heptapeptides.. Bioorganic & medicinal chemistry, 106, 117735. https://doi.org/10.1016/j.bmc.2024.117735