New small molecule drug for lowering cholesterol

Cleveland researchers detail a new oral drug that lowers cholesterol by 70% in animal models.

After statins, the next leading class of medications for managing cholesterol 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 administered as injections, creating barriers to their use.

Longevity.Technology: Having high cholesterol can increase the risk of heart and circulatory diseases such as heart attack, stroke and vascular dementia, but a new study from investigators at University Hospitals (UH) and Case Western Reserve University School of Medicine details an orally administered small-molecule drug that reduces PCSK9 levels and lowers cholesterol in animal models by 70%. Published in Cell Reports, the findings represent a previously unrecognised strategy for managing cholesterol and may also impact cancer treatments.

Cardiovascular disease ranking as the world’s number one killer, so it’s no surprise that a significant amount of research into potential therapeutic options is ongoing; just last week we looked at Cyclarity’s rationally-designed cyclodextrin molecules that remove arterial plaque by clearing the non-degradable oxidised cholesterol and which can be used in conjunction with statins for a broad-spectrum approach. Our report into Cyclarity’s new platform comes out next week, so stay tuned!

“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 Jonathan S Stamler, MD, senior author and President, Harrington Discovery Institute at UH.

“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 [1].”

Study Findings

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. This means that 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, allowing more blood to get to struggling heart muscles. In the new study, Stamler and colleagues showed that nitric oxide can also target and inhibit PCSK9, thus lowering cholesterol. They were able to identify a small molecule drug that functions to increase nitric oxide inactivation of PCSK9. Mice treated with the drug displayed a 70% reduction in LDL “bad” cholesterol [2].

Beyond Cholesterol to Cancer

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 [2].

“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 Stamler. “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 [1].”

[1] https://news.uhhospitals.org/news-releases/cleveland-researchers-new-oral-cholesterol.htm
[2] https://www.cell.com/cell-reports/fulltext/S2211-1247(22)01394-8

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