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A new brain‐penetrant glucosylceramide synthase inhibitor as potential Therapeutics for Gaucher disease
Author(s) -
Fujii Takahiro,
Tanaka Yuta,
Oki Hideyuki,
Sato Sho,
Shibata Sachio,
Maru Takamitsu,
Tanaka Yuta,
Tanaka Maiko,
Onishi Tomohiro
Publication year - 2021
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.15492
Subject(s) - glycosphingolipid , substrate reduction therapy , central nervous system , ceramide , biochemistry , penetrant (biochemical) , chemistry , moiety , pharmacology , disease , biology , stereochemistry , medicine , neuroscience , enzyme replacement therapy , organic chemistry , apoptosis
Gaucher disease (GD), the most common lysosomal storage disorders, is caused by GBA gene mutations resulting in glycosphingolipids accumulations in various tissues, such as the brain. While suppressing glycosphingolipid accumulation is the central strategy for treating peripheral symptoms of GD, there is no effective treatment for the central nervous system symptoms. As glycosphingolipid biosynthesis starts from ceramide glycosylation by glucosylceramide synthase (GCS), inhibiting GCS in the brain is a promising strategy for neurological GD. Herein, we discovered T‐036, a potent and brain‐penetrant GCS inhibitor with a unique chemical structure and binding property. T‐036 does not harbor an aliphatic amine moiety and has a noncompetitive inhibition mode to the substrates, unlike other known inhibitors. T‐036 exhibited sufficient exposure and a significant reduction of glucosylsphingolipids in the plasma and brain of the GD mouse model. Therefore, T‐036 could be a promising lead molecule for treating central nervous system symptoms of GD.