Antibacterial, antitumor and hemolytic activities of α-helical antibiotic peptide, P18 and its analogs

• Published in: The journal of peptide research Vol. 58; no. 6; pp. 504 - 514
• Main Authors: Shin, S.Y., Yang, S.-T., Park, E.J., Eom, S.H., Song, W.K., Kim, J.I., Lee, S.-H., Lee, M.K., Lee, D.G., Hahm, K.-S., Kim, Y.
• Format: Journal Article
• Language: English
• Published: Copenhagen, Denmark Munksgaard 01-12-2001
• Subjects: Amino Acid Sequence; Amino Acid Substitution; Animals; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; antibiotic activity; Antimicrobial Cationic Peptides - chemistry; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; cell selectivity; Cells, Cultured; Circular Dichroism; Drug Design; Drug Screening Assays, Antitumor; Hemolysis; Humans; Mice; Micelles; Microbial Sensitivity Tests; Molecular Sequence Data; P18; Peptide Fragments - chemistry; Pro kink; Protein Structure, Secondary; Structure-Activity Relationship; α-helical antibiotic peptide
• ISSN: 1397-002X; 1399-3011
• DOI: 10.1034/j.1399-3011.2001.00934.x

: The α‐helical antibiotic peptide (P18: KWKLFKKIPKFLHLAKKF‐NH2) designed from the cecropin A(1–8)–magainin 2 (1−12) hybrid displayed strong bactericidal and tumoricidal activity without inducing hemolysis. The effect of the Pro9 residue at central position of P18 on cell selectivity was investigated by Pro9 → Leu or Pro9 → Ser substitution. Either substitution markedly reduced the antibacterial activity of P18 and increased hemolysis, although it did not significantly affect cytotoxicity against human transformed tumor and normal fibroblast cells. These results suggest that a proline kink in α‐helical antibiotic peptide P18 serves as a hinge region to facilitate ion channel formation on bacterial cell membranes and thus plays an important role in providing high selectivity against bacterial cells. Furthermore, to investigate the structure−antibiotic activity relationships of P18, a series of N‐ or C‐terminal deletion and substitution analogs of P18 were synthesized. The C‐terminal region of P18 was related to its antibiotic activity and α‐helical conformation on lipid membranes rather than N‐terminal one. Higher α‐helicity of the peptides was involved in the hemolytic and antitumor activity rather than antibacterial activity. Except for [L9]‐P18 and [S9]‐P18, all the designed peptides containing a Pro residue showed potent antibacterial activity, although they did not induce a cytolytic effect against human erythrocyte and normal fibroblast cells at the concentration required to kill bacteria. In particular, P18 and some analogs (N‐1, N‐2, N‐3, N‐3L and N‐4L) with potent bactericidal and tumoricidal activity and little or no normal cell toxicity may serve as an attractive candidate for the development of novel anti‐infective or antitumor agents.