# Evaluation of GlcNAc-Configured Glycomimetics as Pharmacological Chaperones of NAGLU for the Treatment of Mucopolysaccharidosis IIIB

## TL;DR

Researchers tested GlcNAc-based molecules as potential treatments for a rare genetic disorder called Sanfilippo B syndrome by enhancing enzyme activity.

## Contribution

The study identifies MK 8719 as a promising pharmacological chaperone for NAGLU in mucopolysaccharidosis IIIB.

## Key findings

- MK 8719 significantly increased NAGLU activity in fibroblast cells from four MPS IIIB patients.
- MK 8719 prevented the accumulation of glycosaminoglycans in affected cells.
- Molecular docking and thermal shift assays supported glycomimetic binding to NAGLU.

## Abstract

The interaction of a set of four N-acetyl-glucosamine (GlcNAc) glycomimetics with human N-acetyl-glucosaminidase (NAGLU), the genetically defective enzyme in patients suffering from mucopolysaccharidosis (MPS) IIIB, also known as Sanfilippo B syndrome, was investigated to identify potential pharmacological chaperones. Glycomimetic–NAGLU binding was initially studied by molecular docking simulations and a thermal shift assay. The effects of the glycomimetics on NAGLU activity enhancement were studied in fibroblast cells from seven MPS IIIB patients. A significant increase in NAGLU activity in four cell lines in the presence of glycomimetic MK 8719, a molecule tested in a Phase 1 study in healthy volunteers to treat Alzheimer’s disease, was demonstrated. Furthermore, MK 8719 prevented the increase in glycosaminoglycan (GAG) levels in four MPS IIIB fibroblast cells, suggesting that this molecule may be worth investigating further as a pharmacological chaperone for MPS IIIB. These results represent an important contribution towards the development of a specific therapy for MPS IIIB.