کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
1932345 | 1050578 | 2010 | 4 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: Palmitoyl:protein thioesterase (PPT1) inhibitors can act as pharmacological chaperones in infantile Batten disease Palmitoyl:protein thioesterase (PPT1) inhibitors can act as pharmacological chaperones in infantile Batten disease](/preview/png/1932345.png)
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: βAGDap(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.
Journal: Biochemical and Biophysical Research Communications - Volume 395, Issue 1, 23 April 2010, Pages 66–69