Rationally designed PMAP-23 derivatives with enhanced bactericidal and anticancer activity based on the molecular mechanism of peptide–membrane interactions
Helix (gastropod)
Cathelicidin
DOI:
10.1007/s00726-023-03290-5
Publication Date:
2023-06-13T10:02:23Z
AUTHORS (3)
ABSTRACT
Abstract Antimicrobial peptides (AMPs) are a crucial component of the natural defense system that the host employs to protect itself against invading pathogens. PMAP-23, a cathelicidin-derived AMP, has potent and broad spectrum antimicrobial activity. Our earlier studies led us to hypothesize that PMAP-23 adopts a dynamic helix-hinge-helix structure, initially attaching to membrane surfaces through the N-helix and subsequently inserting the C-helix into the lipid bilayer. Here, we rationally designed PMAP-NC with increased amphipathicity and hydrophobicity in the N- and C-helix, respectively, based on the hypothesis of the interaction of PMAP-23 with membranes. Compared to the parental PMAP-23, PMAP-NC showed 2–8 fold improved bactericidal activity against both gram-positive and gram-negative strains with fast killing kinetics. Fluorescence studies demonstrated that PMAP-NC largely disrupted membrane integrity, indicating that efficiency and kinetics of bacterial killing are associated with the membrane permeabilization. Interestingly, PMAP-NC exhibited much better anticancer activity against tumor cells than PMAP-23 but displayed low hemolytic activity against human erythrocytes. Collectively, our findings suggest that PMAP-NC, with the structural arrangement of an amphipathic helix–hinge–hydrophobic helix that plays a critical role in rapid and efficient membrane permeabilization, can be an attractive candidate for novel antimicrobial and/or anticancer drugs.
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