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U18666A (also known as 3-beta-(2-(diethylamino)ethoxy)androst-5-en-17-one) is a cell-permeable, cationic amphiphilic androstenolone derivative that serves as a widely used research tool in lipid biology. It primarily acts as an inhibitor of intracellular cholesterol trafficking and biosynthesis. U18666A directly binds to the sterol-sensing domain of Niemann-Pick C1 (NPC1) protein, blocking the egress of low-density lipoprotein (LDL)-derived cholesterol from late endosomes and lysosomes, thereby mimicking the phenotype of Niemann-Pick disease type C. Additionally, U18666A inhibits key enzymes in the cholesterol biosynthesis pathway, including lanosterol synthase (LSS), delta-24-cholesterol reductase (DHCR24), and 3-beta-hydroxysteroid-Delta(8),Delta(7)-isomerase (EBP). Due to its ability to disrupt cholesterol homeostasis and endosomal trafficking, U18666A is extensively utilized in vitro to study lysosomal storage disorders, viral entry and replication (such as Ebola, dengue, and hepatitis C viruses), and the role of cholesterol in neurodegenerative diseases and exosome biogenesis.
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