PCSK9

Proprotein convertase subtilisin/kexin type 9 (PCSK9), is an is_associated_with::enzyme that in humans is encoded by the PCSK9 is_associated_with::gene. Similar genes (orthologs) are found across many species.

PCSK9 is inactive when first synthesized, because a section of peptide chains blocks their activity; proprotein convertases remove that section to activate the enzyme.

PCSK9 has medical significance because it acts in cholesterol is_associated_with::homeostasis. Drugs that can block PCSK9, thus lowering is_associated_with::low-density lipoprotein cholesterol (LDL-C), began Phase III clinical trials in 2012 to assess their safety and efficacy in humans, and to determine if they can improve outcomes in heart disease.

PCSK9 was initially known as NARC-1.

Function
This gene encodes a proprotein convertase belonging to the is_associated_with::proteinase K subfamily of the secretory is_associated_with::subtilase family. The encoded protein is synthesized as a soluble is_associated_with::zymogen that undergoes autocatalytic intramolecular processing in the is_associated_with::endoplasmic reticulum. The protein may function as a proprotein convertase.

This protein plays a major regulatory role in is_associated_with::cholesterol homeostasis. PCSK9 binds to the epidermal growth factor-like repeat A (EGF-A) domain of the low-density lipoprotein receptor (LDLR), inducing LDLR degradation. Reduced LDLR levels result in decreased metabolism of LDL-C, which could lead to hypercholesterolemia.

PCSK9 may also have a role in the differentiation of cortical neurons.

Clinical significance
Variants of PCSK9 can reduce or increase circulating cholesterol.

LDL-C is removed from the blood when it binds to an LDLR on the surface of liver cells, and is taken inside the cells. When PCSK9 binds to an LDLR, the receptor is destroyed along with the LDL particle. But if PCSK9 does not bind, the receptor can return to the surface of the cell and remove more cholesterol.

Other variants are associated with a rare autosomal dominant is_associated_with::familial hypercholesterolemia (HCHOLA3). The mutations increase its protease activity, reducing LDLR levels and preventing the uptake of cholesterol into the cells.

As a drug target
Drugs can inhibit PCSK9, leading to lowered circulating cholesterol. Since LDL is considered a risk factor for is_associated_with::cardiovascular disease like heart attacks, it is plausible that these drugs may also reduce the risk of such diseases. Clinical studies, including phase III clinical trials, are now underway to describe the effect of PCSK9 inhibition on cardiovascular disease, and the safety and efficacy profile of the drugs. Among those inhibitors under development in December 2013 were the antibodies is_associated_with::alirocumab, is_associated_with::evolocumab, 1D05-IgG2 (Merck), RG-7652 and LY3015014, as well as the is_associated_with::RNAi therapeutic ALN-PCS02.

Monoclonal antibodies
A number of is_associated_with::monoclonal antibodies that bind to PCSK9 near the catalytic domain that interact with the LDLR and hence inhibit the function of PCSK9 are in clinical trials as of 2014. These include is_associated_with::evolocumab (is_associated_with::Amgen), is_associated_with::bococizumab (is_associated_with::Pfizer), and is_associated_with::alirocumab (is_associated_with::Aventis/is_associated_with::Regeneron).

A is_associated_with::meta-analysis of 24 clinical trials has shown that monoclonal antibodies against PCSK9 can reduce cholesterol, cardiac events and all-cause mortality.

A possible side effect of the monoclonal antibody might be irritation at the injection site. Before the infusions, participants received oral corticosteroids, histamine receptor blockers, and acetaminophen to reduce the risk of infusion-related reactions, which by themselves will cause several side effects.

Peptide mimics
Peptides that mimick the EGFA domain of the LDLR that binds to PCSK9 have been developed to inhibit PCSK9.

Gene silencing
The PCSK9 is_associated_with::antisense oligonucleotide increases expression of the LDLR and decreases circulating total cholesterol levels in mice. A locked nucleic acid reduced PCSK9 is_associated_with::mRNA levels in mice.

Initial clinical trials showed positive results of ALN-PCS, which acts by means of is_associated_with::RNA interference.

Naturally Occuring Inhibitors
The plant alkaloid is_associated_with::berberine inhibits the transcription of the PCSK9 gene. is_associated_with::Annexin A2, an endogenous protein, is a natural inhibitor of PCSK9 activity.