High Selective Performance of Designed Antibacterial and Anticancer Peptide Amphiphiles

• Published in: ACS applied materials & interfaces 2015-08, Vol.7 (31), p.17346-17355
• Main Authors: Chen, Cuixia, Chen, Yucan, Yang, Cheng, Zeng, Ping, Xu, Hai, Pan, Fang, Lu, Jian Ren
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Anti-Bacterial Agents - therapeutic use; Antimicrobial Cationic Peptides - chemistry; Antimicrobial Cationic Peptides - pharmacology; Antimicrobial Cationic Peptides - therapeutic use; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Circular Dichroism; Coculture Techniques; Disease Models, Animal; Escherichia coli - drug effects; Escherichia coli Infections - drug therapy; Fluorescein-5-isothiocyanate - chemistry; Gram-Negative Bacteria - drug effects; Gram-Positive Bacteria - drug effects; HeLa Cells; Hemolysis - drug effects; Hep G2 Cells; Humans; Mice; Microbial Sensitivity Tests; Protein Structure, Secondary
• ISSN: 1944-8244; 1944-8252
• DOI: 10.1021/acsami.5b04547

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) n I-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.