Bioinformatics, Genetics and Cholesterol: The Story of PCSK9

By Jane Cook
March 1, 2022

The Root of Heart Disease

The root cause of most diseases is a disruption of homeostasis, or the delicate balance of all of the biological processes in the body. Heart disease is no exception, and a major cause is a disruption of the balance of cholesterol in the bloodstream.

LDL vs HDL Cholesterol

Cholesterol can be transported by either HDL, which removes excess cholesterol from the body, or LDL, which transports cholesterol around the body and can deposit in the arteries if there is too much. A high HDL to LDL ratio is good for your health, but when that ratio starts to skew towards excess LDL cholesterol, plaques can develop in the arteries and lead to heart attack, stroke and cardiovascular disease.

The Dallas Heart Study and PSCK9

High levels of circulating LDL cholesterol in the blood is dangerous, but the body has a mechanism for LDL cholesterol to be taken up by cells and broken down using the LDL receptor. So why doesn’t this happen? The famous 2006 Dallas Heart Study identified commonalities between patients with low circulating LDL cholesterol levels and a lower risk of heart disease: mutations in their PCSK9 gene.

It turns out that PCSK9 prevents the LDL receptor from taking up circulating LDL cholesterol. So, the study participants with lowered LDL cholesterol and decreased risk of heart disease had loss of function mutations in their PCSK9. Essentially, their PCSK9 did not work properly, so the LDL receptor was free to clear more LDL cholesterol from the bloodstream.

PSCK9: A Therapeutic Target

PCSK9 thus emerged as a promising therapeutic target for the treatment of high cholesterol and cardiovascular disease, and the first line of drugs produced were anti-PCSK9 antibodies. Though relatively effective, antibody therapies can only be administered by injection and tend to be expensive.

Rational Design of a Small Molecule PCSK9 Inhibitor

The missing piece in the PCSK9/LDL cholesterol-targeting space was a small molecule inhibitor of PCSK9, which has the potential for higher efficacy and being more patient-friendly in the form of an oral medication. Merck has developed an extremely promising PCSK9 inhibitor, MK-0616, which is showing PCSK9 and LDL cholesterol-lowering activity in human clinical trials so far.

Merck’s new PCSK9 inhibitor was partially developed using advanced computational techniques for structure-based molecule design and following the well-known “Rule of 5” for orally active biological compounds. The resulting drug is an outstanding proof-of-concept for this emerging technology of computational drug design and screening, combining bioinformatics, machine learning, genetics and organic chemistry.

Outsourcing Bioinformatic Tasks

Discovering new drug targets and designing the molecules to reach them are some of the greatest challenges for biologists that have been aided by the development of new computational methods. Outsourcing bioinformatic tasks to expert service providers eliminates common challenges of using computational methods in the life sciences. Get in touch with us at Bridge Informatics for a free discovery call to discuss your project’s needs.

Jane Cook, Journalist & Content Writer, Bridge Informatics

Jane is a Content Writer at Bridge Informatics, a professional services firm that helps biotech customers implement advanced techniques in management and analysis of genomic data. Bridge Informatics focuses on data mining, machine learning, and various bioinformatic techniques to discover biomarkers and companion diagnostics. If you’re interested in reaching out, please email or


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