Developing small molecules that enhance PCSK9/AnxA2 interaction to inhibit PCSK9 and elevate LDLR levels


Statins to decrease low density lipoprotein cholesterol (LDL-C) are a cornerstone to prevent and treat cardiovascular events. However, inadequate dose response, resistance, and serious side effects are common. Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9), which binds and promotes degradation of LDL receptor (LDLR), has become an alternative or adjunct to statin therapy. PCSK9 inhibition elevates LDLR levels effectively lowering LDL-C. Small molecules inhibiting PCSK9 for oral administration are lacking. Annexin A2 (AnxA2) is a PCSK9 binding protein that inhibits PCSK9-mediated LDLR degradation. Our preliminary genetic analysis of large patient cohorts, and cell-based studies support AnxA2 as a therapeutic target to inhibit PCSK9. This project seeks to develop small molecules that enhance PCSK9/AnxA2 interaction to inhibit PCSK9 and elevate LDLR levels.


Associate Professor Thomas Grewal

Research Location

Sydney Pharmacy School

Program Type



Removal of excess LDL from the circulation is mediated almost entirely by the LDLR in the liver. LDL binds to LDLR at the cell surface of hepatocytes, followed by LDL/LDLR endocytosis. LDL is then targeted to lysosomes for degradation, while LDLR is recycled back to the cell surface to bind more LDL. Familial hypercholesterolemia (FH), an autosomal disorder affecting 1 in 500 Australians, has greatly contributed to identifying therapeutic targets. FH is characterized by elevated plasma LDL and severe risk for coronary heart disease (CHD) in childhood. 60-65% of FH is caused by mutations in the LDLR gene, while 5-10% of FH individuals carry mutations in apolipoprotein B100, the protein component of LDL that interacts with the LDLR. PCSK9 is the third gene associated with FH. FH patients with PCSK9 ‘gain of function' mutations show increased LDLR degradation, less cell surface LDLR and consequently, elevated LDL-C and increased CHD risk. Markedly, healthy carriers of PCSK9 ‘loss of function' mutations have elevated cell surface LDLR and strongly reduced plasma LDL-C levels compared to healthy non-carriers. Moreover, loss of PCSK9 in these healthy individuals reduces CHD risk by 88%12, indicating that strategies targeting pharmaceutical inhibition of PCSK9 are safe. Additional incentive comes from PCSK9 inhibition acting synergistically with statins in FH and non-FH risk patients13, making PCSK9 a prime target for lipid-lowering therapy1,6.

Additional Information

AnxA2, a member of the annexin family, is one of only two currently known natural PCSK9 inhibitors. The N-terminal R1 repeat of AnxA2 binds the PCSK9 C-terminal domain to prevent PCSK9/LDLR interaction and LDLR degradation. Indeed, AnxA2 KO-mice display elevated LDL-C and PCSK9 levels. (1) AnxA2-derived peptides blocking PCSK9/LDLR interaction in vitro and (2) adenoviral AnxA2 overexpression increasing hepatic LDLR levels in vivo suggest therapeutic potential.

Based on our preliminary studies, we hypothesize that (1) small molecules can be developed to enhance AnxA2/PCSK9 interaction leading to decreased LDL-C levels; (2) the AnxA2 V98L mutation decreases the ability of AnxA2 to inhibit PCSK9-mediated LDLR degradation, leading to increased serum LDL-C levels.

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LDL, cholesterol, PCSK9, Annexin A2, small molecules, cardiovascular, diabetes

Opportunity ID

The opportunity ID for this research opportunity is: 1879

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