Modulation of the human cathelicidin dimerization interface separates antimicrobial activity from mammalian membrane disruption
Albin, J. S.; Vithanage, D. A.; Vuong, W.; Johnson, C.; Pentelute, B. L.
Show abstract
The human CAMP gene product LL-37 is a prototypical cationic host defense peptide with potent activity against gram-negative bacteria. The development of LL-37 and other membrane-active host defense peptides as antibiotics, however, is limited in part by their activity against mammalian membranes. To better understand the structural features underlying LL-37 functions, we reconceived of LL-37 as a small protein and systematically ablated the sidechain content of entire surfaces while preserving helical character. This approach revealed that selected modifications within surface m4 retain wild-type levels of activity against gram-negative bacteria while disrupting activity against mammalian membranes by >100-fold. Separation of antimicrobial and mammalian membrane activities mapped primarily to residues I24 and L28, and was attributable to a combination of disrupted oligomerization and decreased hydrophobic content within the dimerization interface. Modulation of the LL-37 dimerization interface thus constitutes a rational pathway by which to engineer derivatives with improved therapeutic potential.
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