title: High Selective Performance of Designed Antibacterial and Anticancer Peptide Amphiphiles.
abstract: Short designed peptide amphiphiles are attractive at killing bacteria and inhibiting cancer cell growth, and the flexibility in their structural design offers a great potential for improving their potency and biocompatibility to mammalian host cells. Amino acid sequences such as G(IIKK)nI-NH2 (n≥3) have been shown to be membrane lytic, but terminal amino acid modifications could impose a huge influence on their performance. We report in this work how terminal amino acid modifications to G(IIKK)3I-NH2 influence its α-helical structure, membrane penetrating ability, and selective actions against different cell types. Deletion of an N-terminal Gly or a C-terminal Ile did not affect their antibacterial activity much, an observation consistent with their binding behavior to negatively charged membrane lipid monolayers. However, the cytotoxicity against mammalian cells was much worsened by the N-terminal Gly deletion, consistent with an increase in its helical content. Despite little impact on the antibacterial activity of G(IIKK)3I-NH2, deletion of both terminal amino acids greatly reduced its antitumor activity. Cholesterol present in tumor cell membrane-mimic was thought to constrain (IIKK)3-NH2 from penetrating into the cancerous membranes, evident from its lowest surface physical activity at penetrating model lipid membranes. On the other hand, its low toxicity to normal mammalian cells and high antibacterial activity in vitro and in vivo made it an attractive antibacterial agent. Thus, terminal modifications can help rebalance the different interactions involved and are highly effective at manipulating their selective membrane responses.
authors.affiliation: †Centre for Bioengineering and Biotechnology, China University of Petroleum (East China), 66 Changjiang West Road, Qingdao 266580, China.
authors.forename: Cuixia
authors.initials: C
authors.lastname: Chen
authors.affiliation: †Centre for Bioengineering and Biotechnology, China University of Petroleum (East China), 66 Changjiang West Road, Qingdao 266580, China.
authors.forename: Yucan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: †Centre for Bioengineering and Biotechnology, China University of Petroleum (East China), 66 Changjiang West Road, Qingdao 266580, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Yang
authors.affiliation: †Centre for Bioengineering and Biotechnology, China University of Petroleum (East China), 66 Changjiang West Road, Qingdao 266580, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Zeng
authors.affiliation: †Centre for Bioengineering and Biotechnology, China University of Petroleum (East China), 66 Changjiang West Road, Qingdao 266580, China.
authors.forename: Hai
authors.initials: H
authors.lastname: Xu
authors.affiliation: ‡Biological Physics Laboratory, School of Physics and Astronomy, University of Manchester, Schuster Building, Manchester M13 9PL, United Kingdom.
authors.forename: Fang
authors.initials: F
authors.lastname: Pan
authors.affiliation: ‡Biological Physics Laboratory, School of Physics and Astronomy, University of Manchester, Schuster Building, Manchester M13 9PL, United Kingdom.
authors.forename: Jian Ren
authors.initials: JR
authors.lastname: Lu
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D002942:Circular Dichroism; D018920:Coculture Techniques; D004195:Disease Models, Animal; D004926:Escherichia coli / Q000187:drug effects; D004927:Escherichia coli Infections / Q000188:drug therapy; D016650:Fluorescein-5-isothiocyanate / Q000737:chemistry; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D006367:HeLa Cells; D006461:Hemolysis / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D051379:Mice; D008826:Microbial Sensitivity Tests; D017433:Protein Structure, Secondary
chemical_list: D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D000970:Antineoplastic Agents; D016650:Fluorescein-5-isothiocyanate
keywords: antibacterial peptide; cell selectivity; helical peptide; membrane penetration; surface pressure