Recent advances in developing PCSK9 inhibitors for lipid-lowering therapy.

Cardiovascular disease is the major cause of death globally, with hypercholesterolemia being an important risk factor. The PCSK9 represents an attractive therapeutic target for hypercholesterolemia treatment and is currently in the spotlight of the scientific community. After autocatalytic activation in the hepatocyte endoplasmic reticulum, this convertase binds to the LDLR and channels it to the degradation pathway. This review gives an overview on the latest developments in the inhibition of PCSK9, including disruption of the protein-protein interaction (PPI) between PCSK9 and LDLR by peptidomimetics, adnectins and monoclonal antibodies and the suppression of PCSK9 expression by small molecules, siRNA and genome editing techniques. In addition, we discuss alternative approaches, such as anti-PCSK9 active vaccination and heparin mimetics.