USA — Researchers at University Hospitals and Case Western Reserve University School of Medicine have discovered an orally administered small-molecule drug that reduces PCSK9 levels and cholesterol by 70% in animal models.

The research, published in the journal Cell Reports, represents a previously unrecognized strategy for managing cholesterol and may also impact cancer treatments.

After statins, the next leading class of medications for managing cholesterol are PCSK9 inhibitors, the researchers said.

These highly effective agents help the body pull excess cholesterol from the blood, but unlike statins, which are available as oral agents, PCSK9 inhibitors can only be administered as shots, creating barriers to their use.

Low-density lipoprotein (LDL) receptors, which sit on the surface of liver cells and remove cholesterol from the blood, lowering serum levels, are central to cholesterol regulation.

PCSK9 regulates the number of LDL receptors in the bloodstream by marking them for degradation. Therefore, agents that inhibit PCSK9 increase the number of LDL receptors that remove cholesterol.

As a result, PCSK9 inhibitors increase the number of LDL receptors that remove cholesterol.

PCSK9 inhibitors were discovered in a group of people who had genetic mutations that caused them to have extremely low cholesterol levels.

Researchers studied this rare population and discovered that their mutation had no negative health effects other than the beneficial effect on their lipids.

PCSK9 inhibitors, work by suppressing genes that slow the production of cholesterol receptors in the liver.

More receptors that are free to emerge and act like sponges can soak up LDL cholesterol and lower its levels in the blood with these medications.

In the new study, Prof. Stamler and colleagues show that nitric oxide can also target and inhibit PCSK9, thus lowering cholesterol.

They identified 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.

Nitric oxide is a molecule that is known to prevent heart attacks by dilating blood vessels, the researchers said.

Furthermore, the findings may have an impact on cancer patients, as emerging evidence suggests that targeting PCSK9 can improve the efficacy of cancer immunotherapies.

PCSK9 not only targets LDL receptors for degradation, it also mediates the degradation of Major Histocompatibility Complex (MHC) Class I on lymphocytes, which is used for recognition of cancer cells,” said Jonathan Stamler, MD, senior author, professor of medicine and biochemistry at University Hospitals and Case Western Reserve

PCSK9 is effectively preventing your lymphocytes from recognizing 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,” he added.

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