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Editing N-Glycan Site Occupancy With Small-Molecule Oligosaccharyltransferase Inhibitors

Editing N-Glycan Site Occupancy With Small-Molecule Oligosaccharyltransferase Inhibitors

Natalia Rinis, Jennifer E Golden, Caleb D Marceau, Jan E Carette, Michael C Van Zandt, Reid Gilmore, Joseph N Contessa

Cell Chem Biol. 2018 Oct 18;25(10):1231-1241.e4.

PMID: 30078634

Abstract:

The oligosaccharyltransferase (OST) is a multisubunit enzyme complex that N-glycosylates proteins in the secretory pathway and is considered to be constitutive and unregulated. However, small-molecule OST inhibitors such as NGI-1 provide a pharmacological approach for regulating N-linked glycosylation. Herein we design cell models with knockout of each OST catalytic subunit (STT3A or STT3B) to screen the activity of NGI-1 and its analogs. We show that NGI-1 targets the function of both STT3A and STT3B and use structure-activity relationships to guide synthesis of catalytic subunit-specific inhibitors. Using this approach, pharmacophores that increase STT3B selectivity are characterized and an STT3B-specific inhibitor is identified. This inhibitor has discrete biological effects on endogenous STT3B target proteins such as COX2 but does not activate the cellular unfolded protein response. Together this work demonstrates that subsets of glycoproteins can be regulated through pharmacologic inhibition of N-linked glycosylation.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP790702577	NGI-1		790702-57-7	Price

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