摘要 |
The present invention provides peptides corresponding to all or a portion of amino acid residues 12-26 of human p53 protein, which peptides are lethal to malignant or transformed cells when fused to a membrane-penetrating leader sequence. In order to reduce proteolysis of a subject peptide, one or more D-amino acids may be substituted for the corresponding L-amino acids in the p53 portion and/or the membrane-penetrating leader of a subject peptide. Further, a pseudopeptide bond or a retro-inverso pseudopeptide bond may be substituted for one or more peptide bonds in either or both of the p53 sequence or membrane-penetrating leader sequence in order to render a subject peptide less susceptible to proteolysis. In addition, both the membrane penetrating leader sequence and the p53 portion of a subject peptide may comprise retro-inverso, and partially modified retro-inverso isomers. Such isomers are less susceptible to proteolysis and therefore have prolonged half-lives. The subject peptides are useful in treating neoplastic disease in an animal, preferably a human. Also provided are pharmaceutical compositions comprising the subject peptides admixed with a pharmaceutical acceptable carrier. Methods of treating neoplastic disease in a patient by administering a subject peptide fused at its carboxy terminal end to a membrane-penetrating leader sequence are also provided as are methods of assessing the level of effectiveness of a subject peptide in killing malignant, transformed, or neoplastic cells in vitro. |