New oral drug discovery for treatment of cholesterol

November 19, 2022

New oral drug discovery for treatment of cholesterolOne of the primary forms of medications for managing cholesterol are known as PCSK9 inhibitors, which are delivered via injections, helping the body pull excess cholesterol from the blood. US investigators at University Hospitals (UH) and Case Western Reserve University School of Medicine have created an orally administered small-molecule drug that reduces PCSK9 levels – the new drugs are similar to orally-administered statin, and can reduce the cholesterol levels in animal models by 70%.

Central to cholesterol regulation are LDL receptors, which sit at the surface of liver cells and remove cholesterol from the blood, thereby lowering serum levels. PCSK9 in the bloodstream controls the number of LDL receptors by marking them for degradation. Therefore, agents that inhibit PCSK9 increase the number of LDL receptors that remove cholesterol.

Nitric oxide is a molecule that is known to prevent heart attacks by dilating blood vessels. In the new study, Dr. Jonathan S. Stamler, Distinguished Professor of Cardiovascular Innovation, and Professor of Medicine and Biochemistry at UH and Case Western Reserve School of Medicine, and colleagues show that nitric oxide can also target and inhibit PCSK9, thus lowering cholesterol. They identify a small molecule drug that functions to increase nitric oxide inactivation of PCSK9. Mice treated with the drug display a 70% reduction in LDL “bad” cholesterol.

“Cholesterol lowering is one of the most important therapies we have to prolong life and protect people from heart disease, which is still the number one cause of morbidity and mortality in the Western world,” said Dr. Stamler. “Statins only lower cholesterol so far. This is a drug class that we think would represent a new way to lower cholesterol, a new way to hit PCSK9.”

In addition to impacting the field of cholesterol metabolism, the findings may impact patients with cancer, as emerging evidence suggests targeting PCSK9 can improve the efficacy of cancer immunotherapies.

“PCSK9 not only targets LDL receptors for degradation, it also mediates the degradation of MHC 1 on lymphocytes, which is used for recognition of cancer cells” said Dr. Stamler. “PCSK9 is effectively preventing your lymphocytes from recognising cancer cells. So, if you inhibit PCSK9, you can boost the body’s cancer surveillance. There may be an opportunity one day to apply these new drugs to that need.”

Category: Features, Pharmaceuticals

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