Lipidated peptides as neuroprotective agents

Abstract

Lipidated neuropeptides based on PrRP31, PrRP20, containing C14 and/or C16 fatty acid, in which sequence of IRPVGRF-NH 2 at the C-terminus is variable in the site of isoleucine, valine and phenylalanine; the fatty acid is bound in position 1 or 11 for PrRP31 or its analog and in position 1 or 7 for PrRP20 or its analog; the fatty acid is bound directly or through a hydrophilic linker X 2 , for use in the treatment and prevention of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), cognitive impairment no dementia (CIND), brain trauma, and neurodegenerative changes and disorders.

1 . Lipidated neuropeptides based on prolactin-releasing peptide, selected from prolactin-releasing peptide 20 (PrRP20), prolactin-releasing peptide 31 (PrRP31) and their analogs,
 wherein in the C-terminal sequence IRPVGRF-NH 2 , one or more of isoleucine, valine and phenylalanine can be replaced by another amino acid;   said PrRP-based neuropeptide containing C14 and/or C16 fatty acid chain, said fatty acid is bound in position 1 or 11 for PrRP31 or its analogs and in position 1 or 7 for PrRP20 or its analogs;   said fatty acid being bound by a bond between an amino acid having at least one free NH 2 , OH or SH group and the carboxylic group of the fatty acid or through a hydrophilic linker X 2  selected from the group comprising polyoxyethylene moiety, arylalkyl moiety, or a saturated or unsaturated, linear or branched C 3 -C8 hydrocarbon chain, wherein some carbon atoms may be replaced by heteroatoms selected from a group comprising N, S, and O; said chain carrying at least one and preferably two amino groups or carboxylic acid groups, one of which may be substituted to form a group selected from: CONH 2 ; NH-polyoxyethylene; COOM 1  wherein M 1  is alkali metal, preferably Na or K; CN; COOR 1 , COR 1 , or CONHR 1  wherein R 1  is selected from a group comprising lower alkyl, arylalkyl, polyoxyethylene, methylpolyoxyethylene, and aminoethylpolyoxyethylene; (CHOH) n R 2  wherein R 2  is H or COOH and n is an integer from 2 to 10; or (CH) n N + R 3 , wherein R 3  is the same or different, selected from H and C 1 -C 4  alkyl;   and the PrRP31 or its analogs may optionally have the amino acid in position 11 replaced by an amino acid having a free NH 2 , OH or SH group, particularly when the fatty acid is bound in position 11 for PrRP31 or its analogs; and the PrRP20 or its analogs may optionally have the amino acid in position 7 replaced by an amino acid having a free NH 2 , OH or SH group in position 7, particularly when the fatty acid is bound in position 7 for PrRP20 or its analogs;   for use in a method of treatment and prevention of neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), cognitive impairment no dementia (CIND), brain trauma, and neurodegenerative changes and disorders.   
     
     
         2 . Lipidated neuropeptides according to  claim 1 , wherein isoleucine can be replaced by phenylglycine or alanine, valine can be replaced by phenylglycine and/or terminal phenylalanine can be replaced by dichlorophenylalanine, pentafluorophenylalanine, nitrophenyalanine, histidine, benzylhistidine, naphtylalanine, tryptofane, pyroglutamic acid, benzylcysteine, benzyl-O-glutamate, tetrachlorophenylalanine, methyl-O-phenylalanine or methyl-NH-phenylalanine, in the sequence of the C-terminal heptapeptide. 
     
     
         3 . Lipidated neuropeptides according to  claim 1 , wherein X 2  is a hydrophilic linker selected from the group comprising β-alanine, γ-aminobutyric acid and γ-glutamic acid. 
     
     
         4 . Lipidated neuropeptides according to  claim 1  having general formulae selected from: 
       
         
           
                 
                 
               
                     
                   (1) 
                 
                     
                   (X)SRTHRHSMEIRTPDINPAWYASRGIRPVGRF-NH 2 , 
                 
                     
                     
                 
                     
                   (2) 
                 
                     
                   (X)SRAHQHSMETRTPDINPAWYTGRGIRPVGRF-NH 2 , 
                 
                     
                     
                 
                     
                   (3) 
                 
                     
                   (X)TPDINPAWYASRGIRPVGRF-NH 2   
                 
                     
                     
                 
                     
                   (4) 
                 
                     
                   (X)TPDINPAWYTGRGIRPVGRF-NH 2 , 
                 
             
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
         wherein X═X 1  or X 1 X 2 ; X 1  being tetradecanoic or hexadecanoic acid, which is bound in a position 1 to an amino acid of the above mentioned peptide chain either directly or through X 2 , X 2  being a hydrophilic linker as defined in  claim 1 , preferably selected from the group consisting of β-alanine, □-amino butyric acid and □-glutamic acid, and 
         wherein in the C-terminal sequence IRPVGRF-NH 2 , one or more of isoleucine, valine and phenylalanine can be replaced by another amino acid; 
         for use in the treatment and prevention, preferably by peripheral administration, of neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), cognitive impairment no dementia (CIND), brain trauma, and neurodegenerative changes and disorders. 
       
     
     
         5 . Lipidated neuropeptides according to the  claim 1  having formulae selected from: 
       
         
           
                 
                 
               
                     
                   (5) 
                 
                     
                   (palm)SRTHRHSMEIRTPDINPAWYASRGIRPVGRF-NH 2   
                 
                     
                   and 
                 
                     
                     
                 
                     
                   (6) 
                 
                     
                   (palm)TPDINPKWYASRGIRPVGRF-NH 2 ; 
                 
             
                
                
                
                
                
                
               
            
           
         
         wherein palm is hexadecanoic acid, and 
         wherein in the C-terminal sequence IRPVGRF-NH 2 , one or more of isoleucine, valine and phenylalanine can be replaced by another amino acid; 
         for use in the treatment and prevention, preferably by peripheral administration, of neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), cognitive impairment no dementia (CIND), brain trauma, and neurodegenerative changes and disorders. 
       
     
     
         6 . Lipidated analogs according to  claim 1  having formulae selected from: 
       
         
           
                 
                 
               
                     
                   (7) 
                 
                     
                   SRTHRHSMEIK(palm)TPDINPAWYASRGIRPVGRF-NH 2 , 
                 
                     
                     
                 
                     
                   (8) 
                 
                     
                   TPDINPK(palm)WYASRGIRPVGRF-NH 2 , 
                 
                     
                     
                 
                     
                   (9) 
                 
                     
                   SRTHRHSMEIKTPDINPAWYASRGIRPVGRF-NH 2 ,  
                 
                     
                   and 
                 
                     
                             |   
                 
                     
                            X 2 (palm) 
                 
                     
                     
                 
                     
                   (10) 
                 
                     
                   TPDINPKWYASRGIRPVGRF-NH 2 ; 
                 
                     
                         | 
                 
                     
                        X 2 (palm) 
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
         wherein palm is hexadecanoic acid and X 2  is □-glutamic acid, and 
         wherein in the C-terminal sequence IRPVGRF-NH 2 , one or more of isoleucine, valine and phenylalanine can be replaced by another amino acid; 
         for use in the treatment and prevention, preferably by peripheral administration, of diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), cognitive impairment no dementia (CIND), brain trauma, and neurodegenerative changes and disorders.