Carbohydrate ligands that bind to antibodies against glycoepitopes of glycosphingolipids

Abstract

The invention relates to carbohydrate ligands and moieties, respectively, mimicking glycoepitopes comprised by glycosphingolipids of the nervous system, particularly glycoepitopes comprised by glycosphingolipids of the cerebroside, the globoside-, the ganglioside- and the sulfoglucuronyl paragloboside type, which are bound by anti-glycan antibodies associated with neurological diseases. The invention further relates to the use of these carbohydrate ligands/moieties, in diagnosis as well as for the treatment of neurological diseases associated with anti-glycan antibodies. In particular, the invention relates to compounds of formula (I) and (II) and to therapeutically acceptable polymers comprising a multitude of these compounds, including polymers with loading of one compound of formula (I) or (II) or combinations of several compounds of formula (I), and/or (II). The compounds of formula (I) are defined as:whereinRI1 is Z orwhereinRI2 is H, SO3H, orwhereinRI3 is H orwhereinRI4 is H orwhereinRI5 and RI6 are independently H orwhereinRI7 is H orand compounds of formula (II) are defined as:whereinRII1 is Z orwhereinRII2 is Z orwherein Z is —N(Ra)-A-B—CH2—(CH2)q—SH, whereinRa is H, C, Ca alkyl, C1-C4-alkoxy, CH2C6H5, CH2CH2C6H5, OCH2C6H5, or OCH2CH2C6H5;A is C1-C7-alkylene, C1-C7-alkoxy, C1-C4-alkyl-(OCH2CH2)pO—C1-C4-alkyl, orC1-C7-alkoxy-Rb, wherein Rb is an optionally substituted aryl or an optionally substituted heteroaryl, and wherein p is 0 to 6, preferably p is 1, 2 or 3, and further preferably p is 1;B is NHC(O), S or CH2;q is 0 to 6, preferably q is 1, 2, 3 or 4, and further preferably q is 1 or 2.

1 . A compound comprising a carbohydrate moiety and a linker Z, wherein said carbohydrate moiety mimics a glycoepitope comprised by a glycosphingolipid of the nervous system, wherein
 said linker Z is —N(R a )-A-B—CH 2 (CH 2 ) q —SH, wherein
 R a  is H, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, CH 2 C 6 H 5 , CH 2 CH 2 C 6 H 5 , OCH 2 C 6 H 5 , or OCH 2 CH 2 C 6 H 5 ; 
 A is C 1 -C 7 -alkylene, C 1 -C 7 -alkoxy, C 1 -C 4 -alkyl-(OCH 2 CH 2 ) p O—C 1 -C 4 -alkyl, or C 1 -C 7 -alkoxy-R b , wherein R b  is an optionally substituted aryl or an optionally substituted heteroaryl, and wherein p is 0 to 6; 
 B is NHC(O), S or CH 2 ; 
 q is 0 to 6; and 
   wherein said linker Z is covalently bound via its —N(R a )-group to the reducing end of said carbohydrate moiety.   
     
     
         2 . The compound of  claim 1 , wherein said compound is a compound of formula (I) or formula (II), wherein formula (I) is 
       
         
           
           
               
               
           
         
         wherein RH is Z or 
       
       
         
           
           
               
               
           
         
         wherein R I2  is H, SO 3 H, or 
       
       
         
           
           
               
               
           
         
         wherein R I3  is H or 
       
       
         
           
           
               
               
           
         
         wherein R I4  is H or 
       
       
         
           
           
               
               
           
         
         wherein R I5  and R I6  are independently H or 
       
       
         
           
           
               
               
           
         
         wherein R I7  is H or 
       
       
         
           
           
               
               
           
         
         and wherein formula (II) is 
       
       
         
           
           
               
               
           
         
         wherein R II1  is Z or 
       
       
         
           
           
               
               
           
         
         wherein R II2  is Z or 
       
       
         
           
           
               
               
           
         
         wherein Z is —N(R a )-A-B—CH 2 (CH 2 ) q —SH, wherein
 R a  is H, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, CH 2 C 6 H 5 , CH 2 CH 2 C 6 H 5 , OCH 2 C 6 H 5 , or OCH 2 CH 2 C 6 H 5 ; 
 A is C 1 -C 7 -alkylene, C 1 -C 7 -alkoxy, C 1 -C 4 -alkyl-(OCH 2 CH 2 ) p O—C 1 -C 4 -alkyl, or C 1 -C 7 -alkoxy-R b , wherein R b  is an optionally substituted aryl or an optionally substituted heteroaryl, and wherein p is 0 to 6; 
 B is NHC(O), S or CH 2 ; and 
 q is 0 to 6. 
 
       
     
     
         3 . The compound of  claim 1 , wherein said compound is a compound of formula (I). 
     
     
         4 . The compound of  claim 1 , wherein said compound is a compound of formula (II). 
     
     
         5 . The compound of  claim 1 , wherein said compound is a compound of formula 4*, 9*, 13*, 17*, 21*, 25*, 29*, 33*, or any one 46*-60*. 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein Z is —N(R a )-A-B—CH 2 (CH 2 ) q —SH, wherein
 R a  is H, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, CH 2 C 6 H 5 , CH 2 CH 2 C 6 H 5 , OCH 2 C 6 H 5 , or OCH 2 CH 2 C 6 H 5 ; 
 A is C 1 -C 7 -alkylene, C 1 -C 7 -alkoxy, C 1 -C 4 -alkyl-(OCH 2 CH 2 ) p O—C 1 -C 4 -alkyl, or C 1 -C 7 -alkoxy-R b , wherein R b  is an optionally substituted aryl or an optionally substituted heteroaryl, and wherein p is 0 to 6; 
 B is NHC(O), S or CH 2 ; and 
 q is 0 to 6. 
 
       
     
     
         6 . The compound of  claim 1 , wherein
 R a  is H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , CH 2 C 6 H 5 , OCH 2 C 6 H 5 ;   A is O(CH 2 ) p CH 2 , (CH 2 ) p CH 2 , CH 2 (OCH 2 CH 2 ) p O—CH 2 , (OCH 2 CH 2 ) p O—CH 2 CH 2  or O(CH 2 ) p C 6 H 5 ; and   B is NHC(O), S or CH 2 .   
     
     
         7 . The compound of  claim 1 , wherein said linker Z is of a formula selected from any one of the formula (a) to (g): 
       
         
           
           
               
               
           
         
       
       wherein p is between 0 and 6, in particular 1, and q is between 0 and 6. 
     
     
         8 . The compound of  claim 1 , wherein said compound is a compound of formula 4, 9, 13, 17, 21, 25, 29, 33, 37, 41, 44, 56, 58 or 77. 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         9 . A polymer composition comprising a multitude of compounds of  claim 1  wherein said compounds are connected to the polymer backbone by way of said linker Z, and wherein said connection is effected via the SH group of said linker Z. 
     
     
         10 . The polymer composition according to  claim 9 , wherein the polymer backbone is selected from an α-amino acid polymer, an acrylic acid or methacrylic acid polymer or copolymer, a N-vinyl-2-pyrrolidone-vinyl alcohol copolymer, a chitosan polymer, and a polyphosphazene polymer. 
     
     
         11 . The polymer composition according to  claim 9 , wherein the molecular weight of the polymer backbone is 1′000 Da to 300′000 Da. 
     
     
         12 . The polymer composition according to  claim 9 , wherein the percentage of loading of the carbohydrate moiety of said compound onto the polymer backbone is between 10 and 90%. 
     
     
         13 . (canceled) 
     
     
         14 . (canceled) 
     
     
         15 . (canceled) 
     
     
         16 . The polymer composition according to  claim 9 , wherein the polymer composition is a microtiter plate or bead coated with the multitude of compounds. 
     
     
         17 . A method of binding autoantibodies against a glycoepitope comprised by a glycosphingolipid of the nervous system in a body fluid sample of a patient, comprising:
 (i) contacting a body fluid sample of a patient with a composition according to  claim 9  comprising carbohydrate moieties that mimic the glycoepitope to bind the autoantibodies present in said body fluid sample; and   (ii) separating the contacted sample from the composition comprising the bound autoantibodies.   
     
     
         18 . The method of  claim 17 , further comprising detecting autoantibodies bound to the composition. 
     
     
         19 . The method of  claim 18 , wherein the polymer composition is a microtiter plate or bead coated with the carbohydrate moieties that mimic the glycoepitope. 
     
     
         20 . The method of  claim 17 , wherein the human bodily fluid is serum, plasma, blood or cerebrospinal fluid. 
     
     
         21 . The method of  claim 17 , wherein the patient is human.