Phosphorylation as an Effective Tool to Improve Stability and Reduce Toxicity of Antimicrobial Peptides

Developing a straightforward and effective strategy to
modify antimicrobial
peptides (AMPs) is crucial in overcoming the challenges posed by their
instability and toxicity. Phosphorylation can reduce toxicity and
improve the stability of AMPs. Based on these, we designed a series
of peptides and their corresponding phosphorylated forms. The results
showed that all phosphorylated peptides displayed reduced toxicity
and enhanced stability compared to their unphosphorylated counterparts.
Among them, W3BipY8-P stood out as the most
promising peptide, exhibiting similar antibacterial activity as its
unphosphorylated analog W3BipY8 but with significantly
reduced hemolytic activity (19-fold decrease), cytotoxicity (3.3-fold
decrease), and an extended serum half-life 6.3 times longer than W3BipY8. W3BipY8-P exerted
bactericidal effects by disrupting bacterial membranes. Notably, W3BipY8-P significantly prolonged the survival of
bacteria-infected animals while its LD50 was 4.2 times
higher than that of W3BipY8. These findings
highlight phosphorylation as an effective strategy for improving the
antimicrobial properties of AMPs.