Cationic antimicrobial peptide (CAP), 6K-F17

Natural α-helical cationic antimicrobial peptide (CAP)sequences are predominantly amphipathic, with only ca. 2% containingfour or more consecutive positively charged amino acids (Lys/Arg).We have designed synthetic CAPs that deviate from these naturalsequences, as typified by the charge-clustered peptide KKKKKKAAFAAWAAFAA-NH2, (termed 6K-F17), which displays high antimicrobialactivity with no toxicity to mammalian cells. We created a series ofpeptides varying in charge patterning, increasing the amphipathiccharacter of 6K-F17 to mimic the design of natural CAPs (e.g.,KAAKKFAKAWAKAFAA-NH2). Amphipathic sequences displayedincreased antimicrobial activity against bacteria but were significantlymore toxic to mammalian cells and more susceptible to proteasedegradation than their corresponding charge-clustered variants,suggesting that amphipathic sequences may be desirable in nature to allow for more versatile functions (i.e., antibacterial,antifungal, antipredator) and rapid clearance from vulnerable host cells. Our approach to clustering of charges may thereforeallow for specialization against bacteria, in concert with prolonged peptide half-life.