PCSK9 as a therapeutic target of dyslipidemia.
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
To summarize approaches proposed to reduce the levels of PCSK9 and/or its activity.


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.
Seidah
Nabil G
NG
Clinical Research Institute of Montreal, Laboratory of Biochemical Neuroendocrinology, 110 Pine Ave West, Montreal, QC, H2W 1R7 Canada. seidahn@ircm.qc.ca
D003545:Cysteine / Q000737:chemistry; D050171:Dyslipidemias / Q000201:enzymology*; D006639:Histidine / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D011487:Protein Conformation; D012697:Serine Endopeptidases / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics
D006639:Histidine; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; D003545:Cysteine