Peptide binding the KLVFF-sequence of amyloid-beta

Abstract

The invention relates to compounds of formula (I) or (II), which are of interest especially for inhibition of polymerization of amyloid β peptide, as model substances for synthesis of amyloid β peptide-ligands, as tools for the identification of other organic compounds with similar functional properties and/or as ligands for detection of amyloid deposits using e.g., positron emission tomography (PET). Formula (II) is: R 1 -A′-Y′-Leu-X′-Z′-B′-R 2 in which X′ means any group or amino acid imparting to the compound according to formula (I) the ability to bind to the KLVFF-sequence in amyloid β peptide, or two amino acids imparting the same ability, but with the proviso that one is not proline; Y′ means any amino acid; Z′ means any non-acidic amino acid; A′ means a direct bond or an α-amino acid bonded at the carboxyl terminal of the α-carboxy group or a di-, tri-, tetra- or pentapeptide bonded at the carboxyl terminal of the α-carboxy group; B′ means a direct bond or an α-amino acid bonded at the α-nitrogen or a di-, tri-, tetra- or pentapeptide bonded at the α-nitrogen of the N-terminal α-amino acid; R 1 is H or —CO—R 3 bonded at the α-amino group of A′; R 2 is H, —OR 4 or NR 5 R 6 , all bonded to the α-carboxyl group of the α-carboxyterminal of B′; R 3 and R 4 are straight or branched carbon chain of 1-4 carbon atoms; R 5 and R 6 are independently H, alkyl, cycloalkyl, aryl or substituted aryl or together are —(CH 2 ) n — where n is 4-5; and R 1 and R 2 together can form a hydrocarbon ring or heterocyclic ring; all α-amino acids being either D- or L-isomers.

We claim:  
     
         1 . A compound having the formula  
       R 1 -A′-Y′-Leu-X′-Z′-B′-R 2    (I)  
       in which 
 X′ means any group or amino acid imparting to the compound of formula (I) the ability to bind to the KLVFF-sequence in amyloid β peptide, or two amino acids imparting the same ability, but with the proviso that one is not proline;  
 Y′ means any amino acid;  
 Z′ means any non-acidic amino acid;  
 A′ means a direct bond or an α-amino acid bonded at the carboxyl terminal of the α-carboxygroup or a di-, tri-, tetra- or pentapeptide bonded at the carboxyl terminal of the α-carboxy group;  
 B′ means a direct bond or an α-amino acid bonded at the α-nitrogen or a di-, tri-, tetra- or pentapeptide bonded at the α-nitrogen of the N-terminal α-amino acid; R 1  is H or —CO—R 3  bonded at the α-amino group of A′; R 2  is H, —OR 4  or NR 5 R 6 , all bound to the α-carboxyl group of the a-carboxyterminal of B′;  
 R 3  is a straight or branched carbon chain of 1-4 carbon atoms;  
 R 4  is a straight or branched carbon chain of 1-4 carbon atoms;  
 R 5  and R 6  independently are H, alkyl, cycloalkyl, aryl or substituted aryl or together are —(CH 2 ) n —, where n is 4-5;  
 R 1  and R 2  together can form a hydrocarbon ring or heterocyclic ring; and  
 all the α-amino acids can be either D- or L-isomers; with the proviso that (I) is not Lys-Leu-Val-Phe-Phe, which exhibits an ability to inhibit polymerization of amyloid β peptide.  
 
     
     
         2 . A compound according to  claim 1 , wherein all the amino acids are D-isomers.  
     
     
         3 . A compound according to  claim 1 , wherein Y′ is Lys.  
     
     
         4 . A compound according to  claim 2 , wherein Y′ is Lys.  
     
     
         5 . A compound according to  claim 3 , wherein Y′ is Lys and Z′ is Phe.  
     
     
         6 . A compound according to  claim 1 , wherein Y′ is Phe.  
     
     
         7 . A compound according to  claim 2 , wherein Y′ is Phe.  
     
     
         8 . A compound according to  claim 1 , wherein X′ is Val-Val.  
     
     
         9 . A compound according to  claim 1 , wherein R 1  is acetyl.  
     
     
         10 . A compound according to  claim 1 , wherein R 1  is H and/or R 2  is H.  
     
     
         11 . Use of a compound of formula  
       R 1 -A′-Y′-Leu-X′-Z′-B′-R 2    (II)  
       in which 
 X′ means any group or amino acid imparting to the compound of formula (II) the ability to bind to the KLVFF-sequence in the amyloid β peptide, or two amino acids imparting the same ability, but with the proviso that one is not proline;  
 Y′ means any amino acid;  
 Z′ means any non-acidic amino acid;  
 A′ means a direct bond or an α-amino acid bonded at the carboxyl terminal of the α-amino acid bonded at the carboxyl terminal of the α-carboxygroup or a di-, tri-, tetra- or pentapeptide bonded at the carboxyl terminal of the α-carboxy group;  
 B′ means a direct bond or an α-amino acid bonded at the α-nitrogen or a di-, tri-, tetra- or pentapeptide bonded at the α-nitrogen of the N-terminal α-amino acid;  
 R 1  is H or —CO—R 3  bonded at the α-amino group of A′;  
 R 2  is H, —OR 4  or NR 3 R 6 , all bound to the α-carboxyl group of the α-carboxyterminal of B′;  
 R 3  is a straight or branched carbon chain of 1-4 carbon atoms;  
 R 4  is a straight or branched carbon chain of 1-4 carbon atoms;  
 R 5  and R 6  independently are H, alkyl, cycloalkyl, aryl or substituted aryl or together are —(CH 2 ) n —, where n is 4-5;  
 R 1  and R 2  together can form a hydrocarbon ring or heterocyclic ring;  
 all the α-amino acids can be either D- or L-isomers;  
 for inhibition of polymerization of amyloid β peptide-ligands for inhibition of polymerization of amyloid β peptide, as a tool for the identification of other organic compounds with similar functional properties or as a ligand in PET (positron emission tomography).  
 
     
     
         12 . Use according to  claim 11 , wherein all the amino acids of the compound are D-isomers.  
     
     
         13 . Use according to  claim 9 , wherein 20 Y′ is Lys.  
     
     
         14 . Use according to  claim 13 , wherein Y′ is Lys and Z′ is Phe.  
     
     
         15 . Use according to  claim 11 , wherein Y′ is Phe.  
     
     
         16 . Use according to  claim 11 , wherein X′ is Val-Val.  
     
     
         17 . Use according to  claim 11 , wherein R 1  is acetyl.  
     
     
         18 . Use according to  claim 11 , wherein R 1  is H and/or R 2  is H.  
     
     
         19 . A compound according to  claim 1  for use as a medicament.  
     
     
         20 . Use of a compound according to  claim 1  for the manufacture of a medicament for the treatment of prevention of amyloidosis.  
     
     
         21 . Use of a compound according to  claim 1  for the manufacture of a medicament for the treatment of prevention of Alzheimer disease associated with amyloidosis.  
     
     
         22 . Use of a compound according to  claim 1  for the manufacture of a medicament for the treatment or prevention of demens in patients with Down's syndrome.  
     
     
         23 . Use of a compound according to  claim 1  for the manufacture of a medicament for the treatment or prevention of Hereditary cerebral hemorrhage with amyloidosis (Dutch type).  
     
     
         24 . Use of a compound according to  claim 1  for the manufacture of a medicament for the prevention of fibril formation of human amyloid protein.  
     
     
         25 . A composition comprising a compound according to  claim 1  and optionally a ligand capable of binding or interacting with the compound according to formula I and a carrier.  
     
     
         26 . A composition according to  claim 25 , which is adapted for injection or oral administration.