Use of colostrinin, constituent peptides thereof, and analogs thereof as modulators of intracellular signaling molecules

Abstract

The present invention provides methods that utilize compositions containing colostrinin, a constituent peptide thereof, an active analog thereof, and combinations thereof, as modulators of intracellular signaling molecules, for example.

1 . A method of modulating an intracellular signaling molecule in a cell, the method comprising contacting the cell with a modulator selected from the group of colostrinin, a constituent peptide thereof, an active analog thereof, and combinations thereof, under conditions effective to accomplish at least one of the following: 
 reduce 4HNE-protein adduct formation;    inhibit 4HNE-mediated glutathione depletion;    inhibit 4HNE-induced activation of p53 protein; or    inhibit 4HNE-induced activation of c-Jun NH2-terminal kinases.    
     
     
         2 . The method of  claim 1  wherein the cell is present in a cell culture, a tissue, an organ, or an organism.  
     
     
         3 . The method of  claim 1  wherein the cell is a mammalian cell.  
     
     
         4 . The method of  claim 3  wherein the cell is a human cell.  
     
     
         5 . The method of  claim 1  wherein the modulator is a constituent peptide of colostrinin.  
     
     
         6 . The method of  claim 5  wherein the modulator is selected from the group  
       
         
           
                 
                 
                 
                 
               
                     
                     
                 
                     
                   MQPPPLP, 
                   (SEQ ID NO:1) 
                     
                 
                     
                     
                 
                     
                   LQTPQPLLQVMMEPQGD, 
                   (SEQ ID NO:2) 
                 
                     
                     
                 
                     
                   DQPPDVEKPDLQPFQVQS, 
                   (SEQ ID NO:3) 
                 
                     
                     
                 
                     
                   LFFFLPVVNVLP, 
                   (SEQ ID NO:4) 
                 
                     
                     
                 
                     
                   DLEMPVLPVEPFPFV, 
                   (SEQ ID NO:5) 
                 
                     
                     
                 
                     
                   MPQNFYKLPQM, 
                   (SEQ ID NO:6) 
                 
                     
                     
                 
                     
                   VLEMKFPPPPQETVT, 
                   (SEQ ID NO:7) 
                 
                     
                     
                 
                     
                   LKPFPKLKVEVFPFP, 
                   (SEQ ID NO:8) 
                 
                     
                     
                 
                     
                   VVMEV, 
                   (SEQ ID NO:9) 
                 
                     
                     
                 
                     
                   SEQP, 
                   (SEQ ID NO:10) 
                 
                     
                     
                 
                     
                   DKE, 
                   (SEQ ID NO:11) 
                 
                     
                     
                 
                     
                   FPPPK, 
                   (SEQ ID NO:12) 
                 
                     
                     
                 
                     
                   DSQPPV, 
                   (SEQ ID NO:13) 
                 
                     
                     
                 
                     
                   DPPPPQS, 
                   (SEQ ID NO:14) 
                 
                     
                     
                 
                     
                   SEEMP, 
                   (SEQ ID NO:15) 
                 
                     
                     
                 
                     
                   KYKLQPE, 
                   (SEQ ID NO:16) 
                 
                     
                     
                 
                     
                   VLPPNVG, 
                   (SEQ ID NO:17) 
                 
                     
                     
                 
                     
                   VYPFTGPIPN, 
                   (SEQ ID NO:18) 
                 
                     
                     
                 
                     
                   SLPQNILPL 
                   (SEQ ID NO:19) 
                 
                     
                     
                 
                     
                   TQTPVVVPPF, 
                   (SEQ ID NO:20) 
                 
                     
                     
                 
                     
                   LQPEIMGVPKVKETMVPK, 
                   (SEQ ID NO:21) 
                 
                     
                     
                 
                     
                   HKEMPFPKYPVEPFTESQ, 
                   (SEQ ID NO:22) 
                 
                     
                     
                 
                     
                   SLTLTDVEKLHLPLPLVQ, 
                   (SEQ ID NO:23) 
                 
                     
                     
                 
                     
                   SWMHQPP, 
                   (SEQ ID NO:24) 
                 
                     
                     
                 
                     
                   QPLPPTVMFP, 
                   (SEQ ID NO:25) 
                 
                     
                     
                 
                     
                   PQSVLS, 
                   (SEQ ID NO:26) 
                 
                     
                     
                 
                     
                   LSQPKVLPVPQKAVPQRDMPIQ, 
                   (SEQ ID NO:27) 
                 
                     
                     
                 
                     
                   AFLLYQE, 
                   (SEQ ID NO:28) 
                 
                     
                     
                 
                     
                   RGPFPILV, 
                   (SEQ ID NO:29) 
                 
                     
                     
                 
                     
                   ATFNRYQDDHGEEILKSL, 
                   (SEQ ID NO:30) 
                 
                     
                     
                 
                     
                   VESYVPLFP, 
                   (SEQ ID NO:31) 
                 
                     
                     
                 
                     
                   FLLYQEPVLGPVR, 
                   (SEQ ID NO:32) 
                 
                     
                     
                 
                     
                   LNF, 
                   (SEQ ID NO:33) 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   MHQPPQPLPPTVMFP, 
                   (SEQ ID NO:34) 
                 
                     
                   and combinations thereof. 
                 
                     
                     
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         7 . A method of down regulating 4HNE-mediated lipid peroxidation in a cell, the method comprising contacting the cell with a modulator selected from the group of colostrinin, a constituent peptide thereof, an active analog thereof, and combinations thereof, wherein: 
 the active analog is an active analog of a constituent peptide of colostrinin selected from the group of SEQ ID NO:1 through SEQ ID NO:34;    the active analog comprises a peptide having an amino acid sequence with at least about 15 percent proline and having at least about 70 percent structural similarity to one or more constituent peptides of colostrinin; and    the active analog does not interfere with cellular uptake of redox-sensitive 2′,7′-dihydro-dichlorofluorescein-diacetate.    
     
     
         8 . Use of a modulator selected from the group of colostrinin, a constituent peptide thereof, an active analog thereof, and combinations thereof in the manufacture of a medicament for: 
 reducing 4HNE-protein adduct formation;    inhibiting 4HNE-mediated glutathione depletion;    inhibiting 4HNE-induced activation of p53 protein; and/or    inhibiting 4HNE-induced activation of c-Jun NH2-terminal kinases.    
     
     
         9 . Use of a modulator selected from the group of colostrinin, a constituent peptide thereof, an active analog thereof, and combinations thereof in the manufacture of a medicament for down regulating 4HNE-mediated lipid peroxidation, wherein the active analog does not interfere with cellular uptake of redox-sensitive 2′,7′-dihydrodichlorofluorescein-diacetate.