Carbohydrate ligands that bind to antibodies against glycoepitopes of glycosphingolipids

Patent metadata

Field	Value
Publication number	US-11091591-B2
Application number	US-201615760398-A
Country	US
Kind code	B2
Filing date	Sep 14, 2016
Priority date	Sep 16, 2015
Publication date	Aug 17, 2021
Grant date	Aug 17, 2021

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, C1-C4-alky, C1-C4alkoxy, CH2C6H5, CH2CH2C6H5, OCH2C6H5, or OCH2CH2C6H5;A is C1-C7-alkylene, C1-C7-alkoxy, C1-C4-alkyl—(OCH2CH2)pO—C1-C4-alkyl, or C1-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.

First claim

The invention claimed is:

1. A polymer comprising:
an α-amino acid polymer backbone; and
at least two carbohydrate moieties of formula 25* or 33* or a salt thereof that mimic a GD1b or GT1a glycoepitope comprised by a glycosphingolipid of the nervous system wherein each carbohydrate moiety is covalently connected to the polymer backbone via a linker Z, wherein:
formula 25* is

formula 33*is

and
the linker Z is selected from any one of formula (a) to (g):

wherein:
p is 0 to 6, and q is 0 to 6; and
Z is covalently bound via its terminal —N atom to the reducing end of said carbohydrate moiety and covalently bound to said a-amino acid polymer backbone via its terminal S— atom and via an optional spacer moiety.

2. The polymer according to claim 1 , wherein the linker Z is of formula (b).

3. The polymer according to claim 1 , wherein the α-amino acid polymer backbone is poly-lysine or poly-ornithine.

4. The polymer according to claim 1 , wherein the percentage of loading of the carbohydrate moieties onto the polymer backbone is between 10 and 90%.

5. The polymer according to claim 1 , wherein the α-amino acid polymer backbone comprises amino acid residues selected from lysine, ornithine, glutamic acid and aspartic acid.

6. The polymer according to claim 3 , wherein the α-amino acid polymer backbone is poly-L-lysine or poly-D-lysine.

7. The polymer according to claim 6 , wherein the carbohydrate moieties are of formula 25*

8. The polymer according to claim 6 , wherein the carbohydrate moieties are of formula 33*

9. The polymer according to claim 7 , wherein the α-amino acid polymer backbone is poly-lysine, and wherein each Z is connected via its terminal S— atom to the —CH 2 group of a spacer moiety of formula —CH 2 CO—, and the spacer moiety is connected to a lysine sidechain via an amide bond.

10. The polymer according to claim 9 , wherein the percentage of loading of the carbohydrate moieties onto the polymer backbone is between 30 and 60%.

11. The polymer according to claim 8 , wherein the α-amino acid polymer backbone is poly-lysine, and wherein each Z is connected via its terminal S— atom to the —CH 2 group of a spacer moiety of formula —CH 2 CO—, and the spacer moiety is connected to a lysine sidechain via an amide bond.

12. The polymer according to claim 11 , wherein the percentage of loading of the carbohydrate moieties onto the polymer backbone is between 30 and 60%.

13. The polymer according to claim 10 , wherein the carbohydrate moieties connected to lysine sidechains of the α-amino acid polymer backbone are of formula 25:

and wherein the remaining lysine sidechains of the α-amino acid polymer backbone are capped with —COCH 2 SCH 2 CH(OH)CH 2 OH.

14. The polymer according to claim 13 , wherein the carbohydrate moieties connected to lysine sidechains of the α-amino acid polymer backbone are of 33:

and wherein the remaining lysine sidechains of the α-amino acid polymer backbone are capped with 2,3-dihydroxypropylthioacetyl.

Assignees

• Univ Basel

Inventors

• Herrendorff Ruben
• Ernst Beat
• Steck Andreas
• Pfister Hélène
• Navarra Giulio

Classifications

• C07H15/12 Primary

  attached to a nitrogen atom of the saccharide radical · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• C08G69/48 Primary

  Polymers modified by chemical after-treatment · CPC title