GRP78 binders

GRP78 binders are a class of small molecule compounds designed to physically bind to the 78 kDa glucose-regulated protein (GRP78), also known as BiP or HSPA5. Developed by researchers at McMaster University, these binders act directly on GRP78 to stabilize its binding with the transcription factor sterol regulatory element-binding protein 2 (SREBP2) within the hepatic endoplasmic reticulum. This stabilization retains SREBP2 in the endoplasmic reticulum, thereby reducing the expression and secretion of proprotein convertase subtilisin/kexin type 9 (PCSK9). Consequently, GRP78 binders show therapeutic potential for the treatment of hyperlipidemia and cardiovascular disease by lowering circulating low-density lipoprotein (LDL) cholesterol levels. Additionally, certain GRP78 binders (such as B07*) have been shown to mitigate anti-GRP78 autoantibody-mediated tissue factor procoagulant activity in endothelial cells, offering a potential strategy to treat atherothrombotic diseases.