期刊
EXPERT OPINION ON THERAPEUTIC TARGETS
卷 13, 期 1, 页码 19-28出版社
TAYLOR & FRANCIS LTD
DOI: 10.1517/14728220802600715
关键词
annexin A2; antisense oligonucleotide; cholesterol metabolism; crystal structure; dyslipidemia; EGF-A; inhibitors; knockdown; knockout; LDL-cholesterol; LDLR; PCSK9; proprotein convertase; silencers
资金
- Canadian Institutes of Health Research [CTP 82946, MOP 36496]
- Canada Chair [201652]
Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9), which promotes degradation of hepatic low density lipoprotein receptor (LDLR), has a role in plasma cholesterol metabolism. Its gene is associated with the development of familial hypercholesterolemia. mRNA silencing or inhibition of PCSK9-induced degradation of LDLR may be used to treat this disease. Objective/methods: To summarize approaches proposed to reduce the levels of PCSK9 and/or its activity. Results/conclusions: mRNA knockdown approaches include the use of antisense oligonucleotides either as soluble phosphorothioates or locked nucleic acids and lipidoid nanoparticles embedded with small interfering RNAs. Passive immunization is also an option. Other strategies include inhibition of the zymogen activation of proPCSK9, or the interaction of PCSK9 with the EGF-A domain of the LDLR. The N-terminal prosegment and the C-terminal Cys-His rich domain (CHRD), are alternative targets. Annexin A2 specifically binds the CHRD and inhibits PCSK9 function, and Annexin A2 peptide mimics could pave the way for the development of novel PCSK9-inhibitory compounds.
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