Structure-activity analysis of the antitumor and hemolytic properties of the amphiphilic alpha-helical peptide, C18G.
The in vitro antitumor and hemolytic activities of analogs of peptide C18G were compared in order to elucidate important structural features which affect cytotoxicity. The sequence of C18G, a basic peptide which can form an amphiphilic alpha-helix, is a derivative of the carboxyl terminus of human platelet factor IV. The results demonstrate that both amphiphilicity and helicity are essential for peptide activity, and that addition of a negatively charged amino acid results in decreased cell lysis. Whereas peptides exhibiting various degrees of potency did not differ with respect to helical content, an increase in peptide hydrophobicity did correlate with an increase in antitumor and hemolytic activity, as well as susceptibility to inhibition by serum. Higher hydrophobicity could be associated with improved ability to insert into the cell membrane. The position or context of specific residues within an amphiphilic peptide can also be important for activity. Furthermore, an increase in tumoricidal activity is not always accompanied by an increase in hemolytic activity or susceptibility to inhibition by serum. Possible reasons for the lower sensitivity of RBCs versus tumor cells to peptide cytotoxicity are discussed. Finally, compared with structurally idealized amphiphilic alpha-helical peptides, non-idealized peptides can possess higher tumoricidal activity, but are less hemolytic and less susceptible to serum inhibition.
Peck-Miller
K A
KA
Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, Washington.
Blake
J
J
Cosand
W L
WL
Darveau
R P
RP
Fell
H P
HP
D000595:Amino Acid Sequence; D023181:Antimicrobial Cationic Peptides; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D001943:Breast Neoplasms; D002277:Carcinoma; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000187:drug effects; D006460:Hemolysin Proteins / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D017433:Protein Structure, Secondary; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D023181:Antimicrobial Cationic Peptides; D000970:Antineoplastic Agents; C081140:C18G peptide; D006460:Hemolysin Proteins; D010455:Peptides