Small molecule can potentially combat many diseases

Disease and treatment 8. jan 2019 3 min Professor Thomas Helleday Written by Kristian Sjøgren

Many diseases and disorders are associated with inflammation in the body. Researchers have developed a small molecule that may counteract inflammatory conditions and can potentially be used for treating diseases ranging from heart disease and non-alcoholic fatty liver disease to stroke and lung infections.

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When our bodies are exposed to oxidative stress, this affects the DNA, which begins to fragment. Luckily, the body has several mechanisms that can repair damaged DNA so it does not break down completely. However, while working hard to repair the DNA, these mechanisms can sometimes trigger inflammation in the body.

This type of inflammation, which can be chronic or temporary, is associated with many diseases. Examples include Crohn’s disease, chronic inflammation of the gastrointestinal tract; non-alcoholic fatty liver disease; autoimmune diseases such as rheumatoid arthritis and psoriasis; cardiovascular diseases; osteoporosis; and some types of cancer.

However, good news may be on the way. New research shows that a tiny molecule (technically called a “small molecule” of about 1 nm) can inhibit one mechanism that contributes to inducing the inflammatory processes. This small molecule can potentially be used to combat all the diseases mentioned above.

“We have discovered a new function of an enzyme that has an important role in repairing DNA. When we suppress its activity, we inhibit the body’s inflammatory response. This may be a very useful tool against many diseases involving an inflammatory response,” explains a researcher behind the new study, Thomas Helleday, Professor, SciLifeLab, Karolinska Institutet, Sweden and Sheffield Cancer Centre, University of Sheffield, United Kingdom.

These results from Thomas Helleday and his colleagues at SciLifeLab have been published in Science. The research was carried out in collaboration between the University of Texas Medical Branch at Galveston, Stockholm University and Uppsala University.

Inflammation occurs when the body repairs itself

Thomas Helleday’s research involves an enzyme called 8-oxoguanine DNA glycosylase (OGG1). OGG1 binds to and repairs DNA, and Thomas Helleday’s research has shown that this promotes the development of inflammation. Among other things, OGG1-deficient mice are resistant to inflammation.

The specific mechanisms in the body’s inflammation response involve the oxidized lesion of DNA, 7,8-dihydro-8-oxoguanine (8-oxoG) , accumulated in conditions of oxidative stress. 8-oxoG lesions are enriched in regions of DNA that are important for gene transcription, and binding of OGG1 to these regions will induce expression of inflammatory mediators and upregulate the immune response.

Thomas Helleday’s therefore hypothesized that inhibiting OGG1 could inhibit the body’s inflammation response in connection with oxidative stress.

“In principle, such a molecule can be used to treat many different conditions associated with chronic inflammation in the body. This also applies to obesity,” says Thomas Helleday.

Cured mice with inflammation in the lungs

The researchers synthesized a small molecule, TH5487, that can bind to and inhibit OGG1 by changing its structure and thereby preventing OGG1 from attaching to and repairing DNA.

To test this molecule, the researchers induced acute lung inflammation in mice by giving them very large quantities of bacterial proteins or tumour necrosis factor-alpha (TNF-alpha), an inflammation-promoting substance naturally present in the body.

The type of lung inflammation the researchers induced in the mice sends the immune response into overdrive and ultimately causes the lungs to collapse because of damage to the alveoli. Half a million people die annually from this type of inflammation, and this also applied to the mice in Thomas Helleday’s laboratory.

However, the experiments on mice showed that giving the mice TH5487 dampened the inflammation and reduced the damage to their lungs.

“This is proof of concept that our molecule functions as we intended. Now we need to investigate this in other virus-induced inflammation situations and in other parts of the body, but it looks promising,” says Thomas Helleday.

May overtake TNF-alpha inhibitors as the world’s best-selling medicine

Although taking newly developed concepts through clinical trials always requires a long time before any drug can be marketed, Thomas Helleday has hopes for his small molecule.

Drugs that inhibit TNF-alpha and thereby reduce inflammation in the body are the world’s best-selling drugs and are used to combat rheumatoid arthritis, inflammatory bowel disease, psoriasis, asthma and many more diseases.

Thomas Helleday thinks that his molecule could potentially be used to combat even more diseases.

He again mentions lung inflammation, against which the molecule has only been tested in mice. Looking ahead, he imagines someone being admitted to a hospital with lung inflammation and being given a type of medicine similar to TH5487 that prevents the lungs from collapsing.

Thomas Helleday and his colleagues are working with such companies as Novo Nordisk on developing medicine of this type.

This molecule may also become useful in strokes.

A blood clot in the brain causes strokes. However, what often kills people is the oxidative stress and inflammation.

“OGG1 is involved in cleaving DNA, and this leads to inflammation. A stroke severely damages DNA, but cleaving all the DNA at the same time is not desirable because this results in an acute inflammatory response that is not good for the brain. Inhibiting OGG1 may therefore counteract some of the effects of a stroke,” says Thomas Helleday.

Small-molecule inhibitor of OGG1 suppresses proinflammatory gene expression and inflammation” has been published in Science. In 2017, the Novo Nordisk Foundation awarded a grant to Thomas Helleday, a principal investigator of the project "Progressing OGG1 inhibitors towards potential candidate drug for inflammation".

The Helleday Laboratory consists of a large team of mixed professions from industry and academia; basic molecular biologists, medicinal chemists, phar...

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