Protein Convertase Subtilisin/Kexin type 9 (PCSK9) is a serine protease primarily expressed in the
liver, which represents the main source of the plasma enzyme. The best characterized function of PCSK9 relates
to the binding to Low-Density Lipoprotein Receptor (LDL-R) in hepatocytes, increasing its endosomal and
lysosomal degradation. This results in the inhibition of LDL-R recycling to the cell surface and therefore the
reduction of the hepatic uptake of LDL, leading to the increase in plasma levels of LDL-cholesterol, a major risk
factor of Cardiovascular Diseases (CVD). Therefore, PCSK9 is an important therapeutic target to reduce LDLcholesterol
levels. PCSK9 inhibition can occur at the level of its interaction with LDL-R as well as at several sites
across the pathway of its intracellular synthesis and secretion. Two fully human mAbs, Alirocumab and Evolocumab,
that selectively bind to PCSK9 and prevent its interaction with the LDL-R, are currently used in the clinical
practice. These mAbs are the most potent cholesterol-lowering agents available today and can decrease LDLcholesterol
levels up to 73% while they also reduce the risk of atherosclerotic CVD. Ongoing research has led to
the development of new PCSK9 inhibitors through genome editing technology (CRISPR-Cas9), siRNA or antisense
oligonucleotide silencing agents, vaccines, mimetic peptides, adnectins, and inhibitors of PCSK9 secretion.
The above inhibitors have been studied in vitro, in animal models in vivo, as well as in phase I and II trials
and have demonstrated an important efficacy profile. Future studies with these agents will demonstrate their possible
clinical value and will further enlighten the various targets and activities of PCSK9 intracellularly and extracellularly,
the underlying mechanisms, as well as the clinical significance of these actions beyond the inhibition
of LDL-R recycling.
Keywords: Αlirocumab, antisense oligonucleotides, bococizumab, εvolocumab, inclisiran, LDL-cholesterol, LDL-receptor, monoclonal antibodies,
PCSK9, siRNA, vaccines.
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