STRUCTURE-ACTIVITY ANALYSIS OF THE ANTITUMOR AND HEMOLYTIC PROPERTIESOF 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 whic h can form an amphiphilic alpha-helix, is a derivative of the carboxyl terminus of human platelet factor IV. The results demonstrate that bo th 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 di d not differ with respect to helical content, an increase in peptide h ydrophobicity did correlate with an increase in antitumor and hemolyti c activity, as well as susceptibility to inhibition by serum. Higher h ydrophobicity could be associated with improved ability to insert into the cell membrane. The position or context of specific residues withi n an amphiphilic peptide can also be important for activity. Furthermo re, an increase in tumoricidal activity is not always accompanied by a n increase in hemolytic activity or susceptibility to inhibition by se rum. Possible reasons for the lower sensitivity of RBCs versus tumor c ells to peptide cytotoxicity are discussed. Finally, compared with str ucturally idealized amphiphilic alpha-helical peptides, non-idealized peptides can possess higher tumoricidal activity, but are less hemolyt ic and less susceptible to serum inhibition. (C) Munksgaard 1994.