Mimicry of the LL-37 N-terminus enhances the activity of short human cathelicidin derivatives

Albin, J. S.; Vithanage, D. A.; Johnson, C.; Pentelute, B. L.

doi:10.1101/2025.05.22.655619

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bioRxiv · 10.1101/2025.05.22.655619

Mimicry of the LL-37 N-terminus enhances the activity of short human cathelicidin derivatives

Albin, J. S.·Vithanage, D. A.·Johnson, C.·Pentelute, B. L.

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Abstract

Issues such as potency and stability limit our ability to realize the potential of host defense peptides (HDPs) to serve as new antibiotics. Informed by our prior structure-activity work, we demonstrate that transposition of an N-terminal biphenyl motif from full-length LL-37 onto the previously-described central activity region (residues 18-29) improves activity against gram-negative bacteria by >16-fold. We further improve upon this lead derivative, termed FF-14, using stabilizing modifications such as D-amino acids and C-terminal amidation as well as selected N-lipidation moieties, and demonstrate the transferability of biphenyl motif activity to longer cathelicidin scaffolds. Mechanistic interrogation reveals that the biphenyl pharmacophore increases both inner and outer membrane permeabilization while promoting helical structure in the 14-mer without directly impacting peptide stability. Inclusion of the LL-37 biphenyl motif is thus a portable strategy for augmenting short cathelicidin activity and better approximating the activity profile of LL-37 itself in short sequences.

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Albin, J. S., Vithanage, D. A., Johnson, C., Pentelute, B. L.. 2025-05-22. Mimicry of the LL-37 N-terminus enhances the activity of short human cathelicidin derivatives. https://doi.org/10.1101/2025.05.22.655619

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