Subtilisin-like proprotein convertase (PCSK) (PCSK)

Subtilisin-type serine proteases, primarily represented by the Proprotein Convertase Subtilisin/Kexin (PCSK) family in humans, are essential enzymes that activate precursor proteins through site-specific proteolysis [Seidah NG, 2012, Nat Rev Drug Discov]. These enzymes, which include members such as Furin and PCSK9, are involved in a wide array of physiological processes including the maturation of hormones, growth factors, and receptors. PCSK9 is a major therapeutic target for cardiovascular disease because it regulates the recycling of the low-density lipoprotein receptor (LDLR); its inhibition significantly lowers circulating LDL-cholesterol levels [Sabatine MS, 2019, Nat Rev Cardiol]. Other members like Furin are exploited by pathogens, such as SARS-CoV-2 and Ebola, for the cleavage and activation of viral envelope glycoproteins, making them targets for antiviral research [Hoffmann M, 2020, Cell]. Consequently, this enzyme family is central to the development of treatments for metabolic disorders, infectious diseases, and certain cancers. The therapeutic landscape includes monoclonal antibodies, siRNA, and emerging small-molecule inhibitors [Seidah NG, 2012, Nat Rev Drug Discov].

Other names

Subtilisin-type serine proteaseSubtilisin-like proprotein convertaseProprotein convertase subtilisin/kexinPCSK familyS8 family proteaseKexin-like protease

The primary mechanism of action for drugs targeting this family involves the inhibition of proteolytic activity or protein-protein interactions. For PCSK9, monoclonal antibodies bind to the enzyme in the circulation, preventing it from interacting with the low-density lipoprotein receptor (LDLR), which prevents LDLR degradation and increases LDL clearance [Sabatine MS, 2019, Nat Rev Cardiol]. For other members like Furin, inhibitors block the cleavage of pro-proteins, such as viral glycoproteins or growth factors, thereby preventing their activation [Seidah NG, 2012, Nat Rev Drug Discov].