Effect of polymers of L-lysine on the cytotoxic action of diphtheria toxin

L-Lysine and poly(L-lysine) polymers of defined sizes were tested for their effect on diphtheria toxin-mediated cytotoxicity of Chinese hamster ovary cells. Poly(L-lysine)8-12 and poly(L-lysine)15 were protective, whereas lysine and lysine polymers of three and four residues were not. The protection by poly(L-lysine)8-12 occurred by affecting the initial toxin receptor interaction. Furthermore, poly(L-lysine)8-12 acted as a competitive inhibitor with an apparent dissociation constant of 6 X 10(-7) M. These observations are consistent with a previously proposed model (Proia et al., J. Biol. Chem. 256:4991-4997, 1981) in which (i) the cationic polyphosphate-binding site (P site) on the B fragment of diphtheria toxin interacts with a putative polyanionic binding site on the toxin receptor, and (ii) the protection of cells from diphtheria toxin by poly(L-lysine) and other polycationic molecules would be the result of the competition between these polycationic molecules and the cationic domain of the diphtheria toxin molecule for the polyanionic toxin-binding site on the cell surface receptor.