Apolipoprotein E-derived antimicrobial peptide analogues with altered membrane affinity and increased potency and breadth of activity.

摘要: Host-derived anti-infective proteins represent an important source of sequences for designing antimicrobial peptides (AMPs). However such are often long and comprise diverse amino acids with uncertain contribution to biological effects. Previously, we identified a simple highly cationic peptide derivative human apolipoprotein E (apoEdp) that inhibited range microorganisms. Here, have dissected the protein chemistry underlying this activity. We report basic residues length around 18 residues were required activity; however, Leu can be substituted by several other without loss activity and, when Phe or Trp, resulted in increased potency. These apoEdp-derived AMPs (apoE-AMPs) showed no cytotoxicity minimal haemolytic activity, active against HIV Plasmodium via extracellular target. CXCR4 CCR5 strains though early stage viral infection upstream fusion, lack inhibition vesicular stomatitis virus G protein pseudotyped HIV-1 suggested anti-HIV was relatively selective. Inhibition invasion hepatocytes observed direct action on integrity attachment cells. The Trp-substituted apoE-AMP adhered mammalian cells irreversibly, explaining its potency; NMR experiments confirmed aromatic also stronger perturbation membrane lipids (relative apoEdp). Our data highlight specific apoEdp (and potentially unrelated AMPs) suggest apoE-AMPs may useful as lead agents preventing stages cellular entry.