# Inhibition of Dermatan Sulfate Epimerase 1 by Substituted Glucuronic Acids

## TL;DR

This study develops and tests new inhibitors for the enzyme DS-epi1, which is involved in the production of glycosaminoglycans linked to various diseases.

## Contribution

The paper introduces a novel class of DS-epi1 inhibitors based on substituted glucuronic acids and evaluates their efficacy.

## Key findings

- Nineteen glucuronic acid derivatives were synthesized and tested, with the most potent showing an IC50 of 42 ± 4 μM.
- Molecular dynamics simulations revealed strong interactions between the inhibitors and the active site of DS-epi1.
- The study highlights the importance of the carboxylic acid group for inhibitor activity.

## Abstract

Dermatan sulfate epimerase 1 (DS-epi1) is a key enzyme
in the biosynthesis
of the glycosaminoglycan chondroitin sulfate/dermatan sulfate, catalyzing
the conversion of glucuronic acid to iduronic acid at the polymer
level. Chondroitin sulfate/dermatan sulfate chains are found on at
least 32 proteoglycans, many of which are implicated in human diseases
and syndromes, as well as in both malignant and normal cell development.
DS-epi1 therefore represents a promising target for drug development,
and recent structural studies have provided insights into its active
site and catalytic mechanism. Here, we report the synthesis and biological
evaluation of inhibitors based on 1,4-disubstituted glucuronic acids.
These compounds were synthesized from glucose through a divergent
approach, yielding 19 derivatives that were tested in a functional
assay. To explore the importance of the carboxylic acid moiety, we
also tested the methyl ester analog and the analogous xylose derivative.
The most potent compound exhibited an IC50 of 42 ±
4 μM. Molecular dynamics simulations showed a strong interaction
with the active site of DS-epi1.