Description

Halogens — fluorine, chlorine, bromine, iodine — are workhorses of medicinal chemistry. They tune molecules with precision that carbon, hydrogen, nitrogen, and oxygen alone cannot. Non-canonical amino acids (ncAAs) let us bring those tools into proteins and peptides.

Halogenated ncAAs increase metabolic stability, tune hydrophobicity without bulk, modulate secondary structure, and improve target engagement.

Here we highlight an exciting breakthrough in antimicrobial peptides! Researchers modified WK₂ with fluorinated non-canonical amino acids (like Fup) to create FuK, boosting serum stability from 225 min to over 1440 min. Outcomes: superior antibacterial activity against MDR bacteria, low toxicity, and strong in vivo efficacy for infections.

Citation: Ouyang et al., 2025

Halogenated amino acids are ubiquitous in small-molecule drug design but have been largely absent from peptide therapeutics. Fluorine, chlorine, and bromine substituents tune hydrophobicity, metabolic stability, and membrane interactions with a precision that natural amino acid side chains may not match.

Fluorinated ncAA modification of the antimicrobial peptide WK2 extended serum stability from 225 minutes to over 1,440 minutes (a 6-fold improvement) while maintaining superior antibacterial activity against multidrug-resistant bacteria. The modified peptide (FuK) showed low toxicity and strong in vivo efficacy against infections (Ouyang et al., 2025).

Halogenated ncAAs represent a particularly practical bridge between small-molecule medicinal chemistry and peptide therapeutics. The same halogen-mediated pharmacological principles that have improved thousands of small-molecule drugs, improved metabolic stability, enhanced membrane permeability, optimised target binding, can now be applied to peptides and proteins through genetic code expansion.

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