去唾液酸糖蛋白受体
PCSK9
前蛋白转化酶
低密度脂蛋白受体
可欣
化学
受体
抗体
生物化学
细胞生物学
体外
脂蛋白
胆固醇
生物
肝细胞
免疫学
作者
Jeffrey T. Bagdanoff,Thomas M. Smith,Martin Allan,Peter H. O’Donnell,Zachary Nguyen,Elizabeth A. Moore,Jason Baird,Shuangxi Wang,Vanitha Subramanian,Bruno Tigani,David O. Nettleton,Lauren G. Monovich,Ian Lewis,Alec N. Flyer,Brian Granda,John W. Blankenship,David Barnes‐Seeman,Kevin B. Clairmont
标识
DOI:10.1016/j.chembiol.2022.12.003
摘要
Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates plasma low-density lipoprotein cholesterol (LDL-C) levels by promoting the degradation of hepatic LDL receptors (LDLRs). Current therapeutic approaches use antibodies that disrupt PCSK9 binding to LDLR to reduce circulating LDL-C concentrations or siRNA that reduces PCSK9 synthesis and thereby levels in circulation. Recent reports describe small molecules that, like therapeutic antibodies, interfere with PCSK9 binding to LDLR. We report an alternative approach to decrease circulating PCSK9 levels by accelerating PCSK9 clearance and degradation using heterobifunctional molecules that simultaneously bind to PCSK9 and the asialoglycoprotein receptor (ASGPR). Various formats, including bispecific antibodies, antibody-small molecule conjugates, and heterobifunctional small molecules, demonstrate binding in vitro and accelerated PCSK9 clearance in vivo. These molecules showcase a new approach to PCSK9 inhibition, targeted plasma protein degradation (TPPD), and demonstrate the feasibility of heterobifunctional small molecule ligands to accelerate the clearance and degradation of pathogenic proteins in circulation.
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