Thursday, February 6, 2014
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
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
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.