Figure 1. PCSK9-mediated regulation of LDLR levels. Proprotein convertase subtilisin kexin type 9 (PCSK9) is highly expressed in the liver and is a validated target for hypercholesterolemia. In Chemistry & Biology, researchers showed that truncated peptide analogs of the epidermal growth factor-like A domain (EGF-A) of the low-density lipoprotein receptor (LDLR) block receptor interaction with PCSK9 and may reduce circulating LDL cholesterol.2

[a] PCSK9 is a protease that is synthesized as an enzyme precursor. Following synthesis, PCSK9 undergoes autocatalytic cleavage, which is required for secretion from the cell. Although cleaved, the two domains of PCSK9 remain together.

[b(1)] When LDL cholesterol binds to LDLR, the receptor ligand is internalized, thus removing LDL cholesterol from circulation. When LDL binds a PCSK9-bound LDLR, the entire complex is internalized. PCSK9 then directs the LDLR to the lysosome, where it is degraded and prevented from recycling to the cell surface. The short peptides block the interaction between PCSK9 and its EGF-A-binding site on LDLR.

[b(2)] If an internalized LDLR is not bound to PCSK9, the receptor is recycled to the cell surface, where it continues to remove LDL cholesterol from circulation.

A number of companies are developing compounds that decrease PCSK9 activity, blocking synthesis of the protein with RNA-targeting therapeutics, mAbs or small molecules that inhibit PCSK9 binding to LDLR.