A novel small-molecule PCSK9 inhibitor E28362 ameliorates hyperlipidemia and atherosclerosis  

作　　者：Wei-zhi Wang Chao Liu Jin-que Luo Li-juan Lei Ming-hua Chen Yu-yan Zhang Ren Sheng Yi-ning Li Li Wang Xin-hai Jiang Tong-mei Xiao Yu-hao Zhang Shun-wang Li Ye-xiang Wu Yang Xu Yan-ni Xu Shu-yi Si 

机构地区：[1]State Key Laboratory of Bioactive Substances and Functions of Natural Medicines,NHC Key Laboratory of Biotechnology for Microbial Drugs,National Center for New Microbial Drug Screening,Institute of Medicinal Biotechnology,Chinese Academy of Medical Sciences and Peking Union Medical College(CAMS&PUMC),Beijing,100050,China [2]Hunan Provincial Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations,Changsha Medical University,Changsha,410219,China [3]Xinjiang Key Laboratory of Uighur Medicine,Xinjiang Institute of Materia Medica,Urumqi,830002,China

出　　处：《Acta Pharmacologica Sinica》2024年第10期2119-2133,共15页中国药理学报（英文版）

基　　金：supported by grants from the CAMS Innovation Fund for Medical Sciences(2021-I2M-1-030,2019-RC-HL-009);the National Natural Science Foundation of China(81973328);Xinjiang Uygur Autonomous Region Key Laboratory Open Project(2022D04017).

摘　　要：Proprotein convertase subtilisin/kexin type 9(PCSK9)binds to the epidermal growth factor precursor homologous domain A(EGF-A)of low-density lipoprotein receptor(LDLR)in the liver and triggers the degradation of LDLR via the lysosomal pathway,consequently leading to an elevation in plasma LDL-C levels.Inhibiting PCSK9 prolongs the lifespan of LDLR and maintains cholesterol homeostasis in the body.Thus,PCSK9 is an innovative pharmacological target for treating hypercholesterolemia and atherosclerosis.In this study,we discovered that E28362 was a novel small-molecule PCSK9 inhibitor by conducting a virtual screening of a library containing 40,000 compounds.E28362(5,10,20μM)dose-dependently increased the protein levels of LDLR in both total protein and the membrane fraction in both HepG2 and AML12 cells,and enhanced the uptake of DiI-LDL in AML12 cells.MTT assay showed that E28362 up to 80μM had no obvious toxicity in HepG2,AML12,and HEK293a cells.The effects of E28362 on hyperlipidemia and atherosclerosis were evaluated in three different animal models.In high-fat diet-fed golden hamsters,administration of E28362(6.7,20,60 mg·kg^(-1)·d^(-1),i.g.)for 4 weeks significantly reduced plasma total cholesterol(TC),triglyceride(TG),low-density lipoprotein-cholesterol(LDL-C)and PCSK9 levels,and reduced liver TC and TG contents.In Western diet-fed ApoE^(-/-)mice(20,60 mg·kg^(-1)·d^(-1),i.g.)and human PCSK9 D374Y overexpression mice(60 mg·kg^(-1)·d^(-1),i.g.),administration of E28362 for 12 weeks significantly decreased plasma LDL-C levels and the area of atherosclerotic lesions in en face aortas and aortic roots.Moreover,E28362 significantly increased the protein expression level of LDLR in the liver.We revealed that E28362 selectively bound to PCSK9 in HepG2 and AML12 cells,blocked the interaction between LDLR and PCSK9,and induced the degradation of PCSK9 through the ubiquitin-proteasome pathway,which finally resulted in increased LDLR protein levels.In conclusion,E28362 can block the interaction between PCSK9 and L

关 键 词：ATHEROSCLEROSIS HYPERLIPIDEMIA PCSK9 inhibitor E28362 LDLR 

分 类 号：R541[医药卫生—心血管疾病]