Team details small-molecule drug that lowers cholesterol by 70% in animal models – ScienceDaily

After statins, the next leading class of drugs for cholesterol management are PCSK9 inhibitors. 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 given as doses, which creates barriers to their use.

Now, a new study by researchers at University Hospitals (UH) and Case Western Reserve University School of Medicine describes an orally administered small molecule drug that reduces PCSK9 levels and lowers cholesterol in animal models by 70%. Posted in Cell ReportsThe findings represent a previously unrecognized strategy for managing cholesterol and may also influence cancer therapies.

“Lowering cholesterol is one of the most important treatments we have to extend life and protect people from heart disease, which remains the number one cause of morbidity and mortality in the Western world,” said Jonathan Stammler, MD, senior author of the study. President of the Harrington Discovery Institute at UH and Robert S. and Silvia K.

“Statins only lower cholesterol so far. This is a class of drugs that we think will represent a new way to lower cholesterol, a new way to hit PCSK9.”


Central to cholesterol regulation is the low-density lipoprotein receptor, which is located on the surface of liver cells and removes 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 clear cholesterol.

Nitric oxide is a molecule known to prevent heart attacks by dilating blood vessels. In the new study, Stammler and colleagues show that nitric oxide can also target and inhibit PCSK9, thereby lowering cholesterol. They have identified a small molecule drug that further inhibits nitric oxide in PCSK9. Mice treated with the drug showed a 70% reduction in bad LDL cholesterol.

Beyond cholesterol to cancer

In addition to affecting the area of ​​cholesterol metabolism, the findings may impact cancer patients, as emerging evidence suggests that targeting PCSK9 could improve the efficacy of cancer immunotherapies.

“PCSK9 not only targets LDL receptors for degradation, but also mediates degradation of MHC 1 on lymphocytes, which is used to recognize cancer cells,” Stammler said. “PCSK9 effectively prevents your lymphocytes from recognizing cancer cells. So, if you inhibit PCSK9, you can enhance your body’s cancer surveillance. There may be an opportunity one day to apply these new drugs to this need.”

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Materials Introduction of University Hospitals Cleveland Medical Center. Note: Content can be modified by style and length.

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