GANGLIOSIDE BIOSYNTHESIS MODULATORS
Provided herein are ganglioside synthesis inhibitors, including modulators of ganglioside glycosylation.
1 . A process for modifying the cellular population of a ganglioside, the process comprising contacting a cell having at least one ganglioside with an effective amount of a selective late-stage ganglioside biosynthesis inhibitor, the selective ganglioside biosynthesis inhibitor being active in a mammalian cell.
2 . The process of claim 1 , wherein the selective late-stage ganglioside biosynthesis inhibitor is a non-carbohydrate inhibitor.
3 . The process of claim 1 , wherein the selective ganglioside biosynthesis inhibitor has a molecular weight of less than 700 g/mol.
4 . The process of claim 1 , wherein the process:
a. reduces the ratio of gangliosides containing mono (α 2,3) sialylation of the (β 1,4) galactose residue in the ceramide linked core compared to gangliosides containing no sialylation of the (β 1,4) galactose residue in the ceramide linked core; and/or
b. reduces the ratio of gangliosides containing mono (α 2,3) sialylation of the (β 1,4) galactose residue in the ceramide linked core compared to gangliosides containing a di-sialylation of the (β 1,4) galactose residue in the ceramide linked core.
5 . The process of claim 1 , wherein the process:
a. reduces the ratio of gangliosides containing di-sialylation of the (β 1,4) galactose residue in the ceramide linked core compared to gangliosides containing no sialylation of the (β 1,4) galactose residue in the ceramide linked core, and/or
b. reduces the ratio of gangliosides containing di-sialylation of the (β 1,4) galactose residue in the ceramide linked core compared to gangliosides containing mono (α 2,3) sialylation of the (β 1,4) galactose residue in the ceramide linked core.
6 . The process of claim 1 , wherein the process reduces the cellular population of GD 1b , GD 2 gangliosides, GD 3 gangliosides, or a combination.
7 . The process of claim 1 , wherein the process reduces the cellular population of GM 1 gangliosides, GM 2 gangliosides, GM 3 gangliosides or a combination.
8 . The process of claim 1 , wherein the selective ganglioside biosynthesis inhibitor inhibits ST3Gal-V transferase, β1-4 GalNAc transferase, β1-3Gal-II transferase ST3Gal-I/II transferase, ST8Sial-I transferase, or a combination thereof.
9 . The process of claim 8 , wherein the selective ganglioside biosynthesis inhibitor directly inhibits the ST3Gal-V transferase, β1-4 GalNAc transferase, β1-3Gal-II transferase ST3Gal-I/II transferase, ST8Sial-I transferase, or a combination thereof.
10 . The process of claim 8 , wherein the selective ganglioside biosynthesis inhibitor indirectly inhibits the ST3Gal-V transferase, β1-4 GalNAc transferase, β1-3Gal-II transferase ST3Gal-I/II transferase, ST8Sial-I transferase, or a combination thereof.
11 . The process of claim 1 , wherein the process reduces the ratio of gangliosides containing a terminal (β1,4) linked GalNAc linked to the (β1,4) galactose residue compared to gangliosides with a (β1,4) galactose lacking a GalNAc.
12 . The process of claim 1 , wherein the process reduces the ratio of gangliosides containing an unmodified (β1,3) linked galactose compared to gangliosides containing a terminal (β1,4) GalNAc.
13 . The process of claim 1 , wherein the cell is a cancer cell or a cell having abnormal ganglioside accumulation.
14 . The process of claim 1 , wherein the cell is present in an individual diagnosed with or suspected of having cancer, inflammation or an inflammatory disease, pathogen entry, or lysosomal storage disease.
15 . The process of claim 14 , wherein the cell is present in an individual diagnosed with or suspected of having melanoma, neuroblastoma, breast cancer or lung cancer.
16 . The process of claim 14 , wherein the cell is present in an individual diagnosed with or suspected of having a lysosomal storage disease, the lysosomal storage disease being Tay-Sachs, Sandhoff, AB variant, GM1 gangliosidosis, or Neimann-Pick.
17 . A composition comprising a population of human serum gangliosides, the population comprising less than 34 mol. % α 2,8-linked sialic acid containing gangliosides.
18 . A composition comprising a population of human serum gangliosides, the population comprising greater than 3 mol. % O series gangliosides.
19 . A composition comprising a population of human serum gangliosides, the population comprising less than 15 mol. % (β1,3) linked galactose containing gangliosides.
20 . A composition comprising a population of human serum gangliosides, the population comprising less than 23 mol. % of (β1,4) linked GalNac gangliosides.