Related Experiment Video

Updated: Jun 24, 2025

In Vitro Enzyme Measurement to Test Pharmacological Chaperone Responsiveness in Fabry and Pompe Disease
10:16

In Vitro Enzyme Measurement to Test Pharmacological Chaperone Responsiveness in Fabry and Pompe Disease

Published on: December 20, 2017

8.1K

Identification of Orthosteric and Allosteric Pharmacological Chaperones for Mucopolysaccharidosis Type IIIB

Juan Camilo Losada1, Heidy Triana1, Egdda Vanegas2

  • 1Institute for the Study of Inborn Errors of Metabolism, Faculty of Science, Pontificia Universidad Javeriana, Cra. 7 No. 43-82 Building 54, Lab 305 A., Bogotá D.C., 110231, Colombia.

Chembiochem : a European Journal of Chemical Biology
|June 3, 2024
PubMed

Insights

Researchers identified novel pharmacological chaperones for Mucopolysaccharidosis type IIIB (MPS IIIB), a rare genetic disorder. Atovaquone and piperaquine show potential to restore enzyme activity, offering new therapeutic avenues for this debilitating disease.

Area of Science:

  • Biochemistry
  • Genetics
  • Pharmacology

Background:

  • Mucopolysaccharidosis type IIIB (MPS IIIB) is a rare, inherited lysosomal storage disease.
  • It results from mutations in the N-acetyl-alpha-glucosaminidase (NAGLU) gene, leading to reduced enzyme activity and heparan sulfate accumulation.
  • Currently, no approved treatments exist for MPS IIIB.

Purpose of the Study:

  • To identify and characterize novel pharmacological chaperones (PCs) for the NAGLU enzyme using a drug repurposing approach.
  • To explore both orthosteric and allosteric binding sites for potential therapeutic molecules.
  • To evaluate the efficacy of identified PCs in restoring NAGLU enzymatic activity.

Main Methods:

  • Computational modeling of substrate interactions within the NAGLU active site.
  • Virtual screening of a human-tested molecule database against orthosteric and allosteric sites.
  • Selection of candidate PCs based on binding affinity, blood-brain barrier permeability, and gastrointestinal absorption.
  • In vitro evaluation of selected PCs in human MPS IIIB fibroblasts.

Main Results:

  • Atovaquone and piperaquine were identified as potential orthosteric and allosteric PCs, respectively.
  • These compounds demonstrated binding to the NAGLU enzyme.
  • The selected PCs showed potential in restoring enzymatic activity in MPS IIIB fibroblasts.

Conclusions:

  • This study presents novel pharmacological chaperones for MPS IIIB.
  • Atovaquone and piperaquine represent promising therapeutic candidates for MPS IIIB.
  • The findings highlight the potential of drug repurposing for developing treatments for protein deficiency diseases.
Keywords:
Drug repurposingMPS IIIBNAGLUPharmacological chaperonesSanfilippo syndrome

More Related Videos

Studies of Chaperone-Cochaperone Interactions using Homogenous Bead-Based Assay06:51

Studies of Chaperone-Cochaperone Interactions using Homogenous Bead-Based Assay

Published on: July 21, 2021

2.8K
Using Caenorhabditis elegans to Screen for Tissue-Specific Chaperone Interactions06:55

Using Caenorhabditis elegans to Screen for Tissue-Specific Chaperone Interactions

Published on: June 7, 2020

2.9K

Related Concept Videos

Molecular Chaperones and Protein Folding03:00

Molecular Chaperones and Protein Folding

The native conformation of a protein is formed by interactions between the side chains of its constituent amino acids. When the amino acids cannot form these interactions, the protein cannot fold by itself and needs chaperones. Notably, chaperones do not relay any additional information required for the folding of polypeptides; the native conformation of a protein is determined solely by its amino acid sequence. Chaperones catalyze protein folding without being a part of the folded protein.
The...
17.9K
Allosteric Proteins-ATCase01:19

Allosteric Proteins-ATCase

Binding sites linkages can regulate a protein's function.  For example, enzyme activity is often regulated through a feedback mechanism where the end product of the biochemical process serves as an inhibitor.
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to  N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis...
5.7K
Ligand Binding and Linkage00:49

Ligand Binding and Linkage

Allosteric proteins have more than one ligand binding site; the binding of a ligand to any of these sites influences the binding of ligands to the other sites. When a protein is allosteric, its binding sites are called coupled or linked.  In the case of enzymes, the site that binds to the substrate is known as the active site and the other site is known as the regulatory site. When a ligand binds to the regulatory site, this leads to conformational changes in the protein that can influence...
4.8K
Lysosomal Hydrolases01:22

Lysosomal Hydrolases

Lysosomes are the site for the degradation of macromolecules and biological polymers released during membrane trafficking events such as secretory, endocytic, autophagic, and phagocytic pathways. The membrane-enclosed area of the lysosome, called the lumen, contains hydrolytic enzymes active in an acidic environment. These acid hydrolases are functional at a pH between 4.5 and 5 and are involved in cellular processes such as cell signaling, energy metabolism, restoration of the plasma membrane,...
3.8K
Protein Folding Quality Check in the RER01:29

Protein Folding Quality Check in the RER

ER is the primary site for the maturation and folding of soluble and transmembrane secretory proteins. The calnexin cycle is a specific chaperone system that folds and assesses the confirmation of N-glycosylated proteins before they can exit the ER lumen. The primary players of this quality check pipeline are the lectins, ER-resident chaperones, and a glucosyl transferase enzyme. In case the calnexin system in the lumen fails to salvage a misfolded protein, it is transported to the cytoplasm...
3.7K
Indirect-Acting Cholinergic Agonists: Chemistry and Structure-Activity Relationship01:29

Indirect-Acting Cholinergic Agonists: Chemistry and Structure-Activity Relationship

Indirect-acting cholinergic agonists are agents that interact with the acetylcholinesterase enzyme in the synaptic cleft, preventing the breakdown of acetylcholine into choline and acetate. Consequently, the concentration of acetylcholine in the synaptic cleft increases. These agonists can be classified into reversible and irreversible inhibitors based on their duration of action.
Reversible inhibitors display short to medium durations of action. Short-acting agents include simple alcohols with...
554