The discovery of PCSK9 inhibitors: A tale of creativity and multifaceted translational research

Atherosclerosis, obesity, andmetabolic syndromeare closely linked and constitute, arguably, themost menacing three conditions to modern society. Thus urgent, concerted efforts at several levels, utilising modern tools, are required to tackle them. Translational research is a rapidly expanding branch of science, dedicated to rapid delivery of discoveries from the bench to the bedside. The growing importance of this specialty in our field is evidenced by the establishment of the International Society of Cardiovascular Translational Research and its dedicated Journal by Nabil Dib and colleagues. The fundamental discovery of the relationship between, lipids, cholesterol and atherosclerosis was made in the 1960s. This led to the discovery of lipid lowering drugs, including statins, which constitute one of the blockbuster drugs of modern times. In spite of that, the toll of the three conditions mentioned above continued almost unabated, particularly in patients with familial hypercholesterolemia (FH) in whom LDL apheresis and/or liver transplantation are needed in many instances to achieve adequate reduction of LDL-cholesterol levels. The landmark discovery of the role of the LDL receptors in lipid clearance by Goldstein and Brown (Figures 1 and 2) earned them the Nobel Prize, and opened the door to further translational research which led to several further discoveries, including that of Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9). In addition to establishing the role of the LDL receptors in clearing LDL-C from the circulation, and that FH is due to a mutation in the LDL receptor gene, Brown and Goldstein described three new cellular processes, including receptor-mediated endocytosis (paving the way for further research into the mechanisms of vesicle transport and cellular trafficking; work for which Rothman, Schekman and Sudhof have recently been awarded the Nobel Prize in Medicine), receptor recycling, and feedback regulation of receptors, which led to discovery of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase and statins. Several years later, the discovery of a major regulatory pathway controlling the number and function of the LDL receptors was made by a large number of researchers working in different