N-LINKED GLYCAN BIOSYNTHESIS MODULATORS
Provided herein are N-linked glycan inhibitors, including modulators of N-linked glycan glycosylation, mannosidase, an N-linked glycan N-acetylglucosaminyl transferase, an N-linked glycan fucosyl transferase, an N-linked glycan galactosyl transferase, an N-linked glycan sialyl transferase, an N-linked glycan sulfotransferase, N-linked glycan glycophosphotransferase or a combination thereof.
1 . A process for modifying the population of N-linked glycans on one or more proteins associated with a cell, the process comprising contacting a cell that produces N-linked glycans with an effective amount of a selective late stage N-linked glycan biosynthesis inhibitor, the selective late stage N-linked glycan biosynthesis inhibitor being active in a mammalian cell.
2 . The process of claim 1 , wherein the selective late stage N-linked glycan biosynthesis inhibitor is a non-carbohydrate inhibitor.
3 . The process of claim 1 , wherein the selective N-linked glycan biosynthesis inhibitor has a molecular weight of less than 700 g/mol.
4 . The process of claim 1 , wherein the process reduces the ratio of complex N-linked glycans to high mannose N-linked glycans.
5 . The process of claim 1 , wherein the process reduces the amount of tri-antennary and tetra-antennary N-linked glycans in the cellular population of N-linked glycan.
6 . The process of claim 1 , wherein the process reduces the cellular population of (β1-6) branching N-linked glycans.
7 . The process of claim 1 , wherein the process reduces the cellular population of poly-N-acetyllactosamine-containing N-glycans.
8 . The process of claim 1 , wherein the process reduces the cellular population of outer-chain polyfucosylation, sialyl Lewis X containing N-glycans, or both.
9 . The process of claim 1 , wherein the selective N-linked glycan biosynthesis inhibitor inhibits GlcNAc-T-V, GlcNAc-T-IV, GlcNAc-T-III, GlcNAc-T-II, or a combination thereof.
10 . The process of claim 9 , wherein the selective N-linked glycan biosynthesis inhibitor indirectly inhibits GlcNAc-T-V, GlcNAc-TIV GlcNAc-T-III, GlcNAc-T-II, or a combination thereof.
11 . The process of claim 9 , wherein the selective N-linked glycan biosynthesis inhibitor directly inhibits GlcNAc-T-V, GlcNAc-T-IV, GlcNAc-T-111, GlcNAc-T-11, or a combination thereof.
12 . The process of claim 1 , wherein the selective N-linked glycan biosynthesis inhibitor inhibits modifications including (α2,3) sialylation, (α2,6) sialylation, (α1,3) fucosylation, 6-sulfation of the terminal galactose, 6-sulfation of the penultimate GlcNAc.
13 . The process of claim 1 , wherein the cell is an inflammatory cell, a cancer cell, an endothelial cell, a cell having abnormal N-linked glycan accumulation, or a cell susceptible to viral and pathogenic infection.
14 . The process of claim 1 , wherein the cell is present in an individual diagnosed with or suspected of having rheumatoid arthritis, Crohn's disease, inflammatory bowel disease, lung cancer, colon cancer, breast cancer, pathogenic angiogenesis, or diabetes.
15 . The process of claim 1 , wherein the cell is present in an individual diagnosed with or suspected of having influenza, HIV, lysosomal storage disease, sialidosis, or fucosidosis.
16 . An N-linked glycanated protein comprising a core protein covalently linked to at least one N-linked glycan, (i) the at least one N-linked glycan comprising a plurality of high mannose, hybrid or complex N-linked glycan structures, and (ii) less than 9 mol % of the plurality of high mannose, hybrid or complex N-linked glycan structures being tri-antennary N-linked glycans, less than 2 mol % of the plurality of high mannose, hybrid or complex N-linked glycan structures being tetra-antennary N-linked glucans, or both.
17 . (canceled)
18 . An N-linked glycanated protein comprising human serum acid alpha-1-glycoprotein N-linked glycanated comprising bi-antennary, tri-antennary and tetra-antennary N-linked glycans, wherein less than 52% (w/w) of the N-linked glycans are the sum of the tri-antennary and tetra-antennary N-linked glycans, less than 12% (w/w) of the N-linked glycans are tetra-antennary, or both.
19 . (canceled)