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.
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