Role of PCSK9 on cholesterol metabolism and beyond: identification of new natural inhibitors

Proprotein convertase subtilisin kexin 9 (PCSK9) is a key regulator of low-density lipoprotein receptor levels and LDL-cholesterol levels. Loss-of-function mutations in PCSK9 gene are associated with hypocholesterolaemia and protection against cardiovascular disease, identifying PCSK9 inhibition as a valid therapeutic approach to manage hypercholesterolaemia and related diseases. Although PCSK9 is expressed mainly in the liver, it is present also in other tissues and organs with specific functions, raising the question of whether a pharmacological inhibition of PCSK9 to treat hypercholesterolaemia and associated cardiovascular diseases might be helpful or deleterious in non-hepatic tissues. For example, PCSK9 is expressed in the vascular wall, in the kidneys, and in the brain, where it was proposed to play a role in vascular calcification, Alzheimer’s disease and neurocognitive process.
The efficacy of anti-PCSK9 mAbs may reach up to 55% LDL-C lowering as monotherapy1 and up to a 61% when added to standard therapy. These mAbs are quite effective but present a few drawbacks: 1) very high costs; 2) must be administered subcutaneously (poor compliance and convenience); 3) can be immunogenic for long term treatments; 4) acts mainly on circulating PCSK9.
The most recent alternative to mAbs that has been recently approved is represented by Inclisiran, a synthetic small interfering RNA (siRNA) conjugated to triantennary N-acetylgalactosamine carbohydrates (siRNA-GalNAc) designed to target PCSK9 mRNA exclusively in the liver.
In recent years, the focus has switched to the development of cheap and orally administrable small-molecule PCSK9 inhibitors, to be used as monotherapy or in combination with statins.
We have recently discovered a family of new small molecules with inhibitory activity on PCSK9 production by human hepatoma cell lines. In addition, we identified interesting natural compounds with potential hypocholesterolemic effect and PCSK9 inhibitory activity. Both approached can be useful to extend the therapeutic role of anti PCSK9 beyond the control of high cholesterol levels but rather vascular calcification and Alzheimer’s disease.