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

Host defense peptides (HDPs) have long been studied as templates for the development of new antibiotic classes, and human HDPs hold unique potential among possible templates due to the evolution of the template peptide as part of the broader human immune system. In this work, we describe the development of lead peptidomimetics based on the human HDP LL-37. Using automated flow peptide synthesis technology, we rapidly generated a series of peptides and peptidomimetics based on our prior structure-activity work in the full-length LL-37 template, which led to the discovery of a modified minimal unit of LL-37 in which potency is enhanced by appending an N-terminal biphenyl clamp from the native sequence to the previously described core activity region. Activity of this lead derivative, termed FF-14, was further improved through the application of D-amino acids and C-terminal amidation as well as selected N-lipidation moieties to the template sequence, providing the foundation for future iteration on a small, highly active derivative of LL-37.