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Inhibiting PCSK9 Self-Proteolysis to Treat Atherosclerosis
2021 Harrington Scholar-Innovator
Atherosclerosis—hardening and narrowing of artery walls caused by a buildup of cholesterol plaques—is a major risk factor for cardiovascular disease and stroke, the leading causes of death in the United States. A primary driver of atherosclerosis is elevated levels of low density lipoprotein (LDL), sometimes called ‘bad cholesterol,' in the blood, and the protoprotein PCSK9 is a contributor to elevated LDL levels. PCSK9 downregulates the hepatic LDL receptor, which clears LDL from the bloodstream. This downregulation raises LDL levels and accelerates atherosclerosis.
Dr. Chorba and his colleagues are pursuing a small molecule approach to inhibit the action of PCSK9 but are challenged by the fact that its biochemical output is difficult to study. Proteolysis (cleaving or breaking down of a protein) is required for PCSK9's effect on the LDL receptor. However, as a single-turnover protease, PCSK9 cleaves only once; afterwards there is no further readout of its protease activity.
Dr. Chorba and his colleagues have developed a cell-based method to evaluate PCSK9's proteolytic activity. They created a 70,000 compound high-throughput screen resulting in hit compounds that act as inhibitors of PCSK9's proteolytic function. The researchers theorize that the development of a lead compound acting by its this novel mechanism of action will increase hepatic LDL receptor function and lower serum LDL.
“I think there are more mechanisms we can use to target PCSK9 than were previously thought,” Dr. Chorba says. “There are individuals who have mutations in PCSK9 where their PCSK9 simply doesn't work. Our strategy, at least in theory, would mirror some of those mutations.”
Dr. John Chorba, a 2021 Harrington Scholar-Innovator from the University of California, San Francisco is revolutionizing the field of Cardiovascular Medicine with a focus on treating atherosclerosis, a leading risk factor for cardiovascular disease and stroke in the United States. Discover how Harrington Discovery Institute empowers innovative scientists like Dr. Chorba to bridge the gap between academic research and clinical application. In this video, Dr. Chorba explains his unique approach to inhibiting PCSK9 self-proteolysis and its potential to lower LDL cholesterol levels, ultimately combating atherosclerosis. This pioneering research could be a game-changer in the fight against heart disease. Support our mission to turn science into life-changing medicine.