Peptides selectively lethal to malignant and transformed mammalian cells

Abstract

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. The subject peptides are thus 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.

What is claimed is:  
     
         1 . A peptide comprising at least about six contiguous amino acids of the amino acid sequence: PPLSQETFSDLWKLL (SEQ ID NO:1), or an analog or derivative thereof, wherein said peptide or analog or derivative thereof is fused to a membrane-penetrating leader sequence and is selectively lethal to malignant or transformed cells.  
     
     
         2 . The peptide of  claim 1  comprising the amino acid sequence PPLSQTFSDLWKLL (SEQ ID NO:1) or an analog or derivative thereof.  
     
     
         3 . The peptide of  claim 1  comprising the amino acid sequence: PPLSQETFS (SEQ ID NO:2) or an analog or derivative thereof.  
     
     
         4 . The peptide of  claim 1  comprising the amino acid sequence: ETFSDLWKLL (SEQ ID NO:3) or an analog or derivative thereof.  
     
     
         5 . The peptide, analog or derivative thereof of any of claims  1 - 4  wherein the leader sequence is located at the carboxyl terminal end of the peptide, analog, or derivative thereof.  
     
     
         6 . The peptide, analog, or derivative thereof of any of claims  1 - 4  wherein the leader sequence is located at the amino terminal end of the peptide, analog, or derivative thereof.  
     
     
         7 . The peptide, analog or derivative thereof of any of claims  1 - 4  wherein the leader sequence comprises predominantly positively charged amino acid residues.  
     
     
         8 . The peptide, analog or derivative thereof of any of claims  1 - 4  wherein the leader sequence is at least one of penetratin, Arg 8 , TAT of HIVI, D-TAT, R-TAT, SV40-NLS, nucleoplasmin-NLS, HIV REV, FHV coat, BMV GAG, HTLV-II (REX), CCMV GAG, P22N, Lambda N, Delta N, yeast PRP6, human U2AF, human C-FOS, human C-JUN, yeast GCN4, or p-vec.  
     
     
         9 . The peptide, analogue, or derivative thereof of  claim 8  wherein the penetratin leader sequence has the amino acid sequence: KKWKMRRNQFWVKVQRG (SEQ ID NO:4).  
     
     
         10 . A pharmaceutical composition comprising at least one of the peptides or analogs or derivatives thereof according to claims  1 - 4  admixed with a pharmaceutically acceptable carrier.  
     
     
         11 . A pharmaceutical composition comprising at least one of the peptides, analogs, or derivatives thereof according to  claim 5  admixed with a pharmaceutically acceptable carrier.  
     
     
         12 . A pharmaceutical composition comprising at least one of the peptides, analogs, or derivatives thereof according to  claim 6  admixed with a pharmaceutically acceptable carrier.  
     
     
         13 . A pharmaceutical composition comprising at least one of the peptides, analogs, or derivatives thereof according to  claim 7  admixed with a pharmaceutically acceptable carrier.  
     
     
         14 . A pharmaceutical composition comprising at least one of the peptides, analogs, or derivatives thereof according to  claim 8  admixed with a pharmaceutically acceptable carrier.  
     
     
         15 . A pharmaceutical composition comprising at feast one of the peptides, analogs, or derivatives thereof according to  claim 9  admixed with a pharmaceutically acceptable carrier.  
     
     
         16 . A method of selectively killing malignant or neoplastic cells in a subject, said method comprising administering to the subject, a therapeutically effective amount of a peptide of at least about six contiguous amino acids of the amino acid sequence: PPLSQETFSDLWKLL (SEQ ID NO:1), or an analog or derivative thereof, wherein a membrane-penetrating leader sequence is fused to the carboxy terminal of said peptide, analog or derivative thereof.  
     
     
         17 . A method of selectively killing malignant or neoplastic cells in a subject, said method comprising administering to the subject, a therapeutically effective amount of at least one peptide of claims  2 ,  3 , or  4  or an analog or derivative thereof, wherein the membrane-penetrating leader sequence is fused to the carboxy terminal end of said peptide or analog or derivative thereof.  
     
     
         18 . A method of selectively killing malignant or neoplastic cells in a subject, said method comprising administering to the subject, a therapeutically effective amount of at least one peptide of  claim 7  wherein the membrane-penetrating leader sequence is fused to the carboxy terminal end of the peptide, analog, or derivative thereof.  
     
     
         19 . A method of selectively killing malignant or neoplastic cells in a subject, said method comprising administering to the subject, a therapeutically effective amount of at least one peptide of  claim 8  wherein the membrane penetrating leader sequence is fused to the carboxy terminal end of the peptide, analog, or derivative thereof.  
     
     
         20 . A method of selectively killing malignant or neoplastic cells in a subject, said method comprising administering to the subject, a therapeutically effective amount of the peptide of  claim 9  or an analog or derivative thereof wherein the penetratin leader sequence is fused to the carboxy terminal end of the peptide or analog or derivative thereof.