Palmitoyl:protein thioesterase (PPT1) inhibitors can act as pharmacological chaperones in infantile Batten disease.

Abstract

Competitive inhibitors of lysosomal hydrolases (pharmacological chaperones) have been used to treat some lysosomal storage diseases which result from mis-sense mutations and mis-folded protein but have not been tried in Batten disease, for which there is no current therapy. We synthesized a large number of novel, non-hydrolyzable competitive inhibitors of palmitoyl:protein thioesterase (PPT1) and showed that some could act as chemical chaperones. One inhibitor (CS38: betaAGDap(Pal)VKIKK) was taken up by lymphoblasts from patients with mutations leading to the T75P/R151X substitutions and enhanced PPT1 activity 2-fold. A similar 2-fold stimulation with another inhibitor (AcGDap(Palm)GG(R)(7)) was observed in patients with a G108R amino acid substitution in PPT1. Residual PPT1 activity in both was thermally unstable at pH 7.4 (but not at 4.7) consistent with a mis-folded, unstable PPT1 degraded by the ER stress response. Patients with null mutations did not respond to the pharmacological chaperones.

• Authors: Glyn Dawson, Christina Schroeder, Philip E Dawson
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 395 Issue 1 Pg. 66-9 (Apr 23 2010) ISSN: 1090-2104 [Electronic] United States
• PMID: 20346914 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: 2010 Elsevier Inc. All rights reserved.

Chemical References

• Enzyme Inhibitors
• Membrane Proteins
• Molecular Chaperones
• Thiolester Hydrolases
• PPT1 protein, human

Topics

• Cell Line
• Enzyme Inhibitors (chemistry, pharmacology, therapeutic use)
• Enzyme Stability (genetics)
• Humans
• Membrane Proteins (antagonists & inhibitors, genetics, metabolism)
• Molecular Chaperones (chemistry, pharmacology, therapeutic use)
• Neuronal Ceroid-Lipofuscinoses (drug therapy, enzymology)
• Point Mutation
• Protein Folding (drug effects)
• Thiolester Hydrolases