Peptaibiotic-inspired antimicrobials based on human cathelicidin
Albin, J. S.; Vithanage, D. A.; Pentelute, B. L.
Show abstract
Mammalian cell toxicity is a major barrier to the development amphipathic helical peptides for antibiotic applications. Toward addressing this limitation, we report here the development of a paired Ala-Aib helix scanning approach to isolate the sidechain-independent effects of helical content on the underlying antimicrobial and hemolytic activities of a model cathelicidin-derived scaffold. Despite the generally accepted premise that cathelicidin helical content correlates with antimicrobial activity, we find that this relationship is species-dependent. Moreover, gains in antimicrobial activity associated with greater helical content generally outpace losses associated with increasing hemolytic activity. Combining these insights with our prior work on the development of oligomerization-deficient cathelicidins, we develop a short Aib-rich cathelicidin derivative with a 32-fold improvement in in vitro therapeutic index over the naturally occurring parent helix. Our results thus introduce principles for the rational design of cathelicidin-derived scaffolds based on differential structural requirements for distinct functions.
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