Friday , March 31 2023

The researchers found a new treatment for pneumonia



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Inflammatory diseases such as COPD and blood poisoning pose a growing threat to public health.

Often, such conditions are the result of a hyperactive immune system.

That's why the molecule's discovery wakes up TH5487 interfere. The molecule has the ability to disarm a protein that proves to play an important role in inflammatory diseases.

The molecule has been shown to inhibit pneumonia in mice.

The discovery was made by researchers at the Karolinska Institutet in Stockholm, the University of Stockholm, the University of Texas, as well as NTNU and Sintef in Trondheim.

Start button for an excessive response

An inflammation is a reaction from the immune system where the purpose is to limit a lesion or infection. But for some, inflammation can hurt:

In those who have a lot of inflammatory diseases, the body produces a lot of ROS signal. It is an abbreviation for "reactive oxygen species" and initiates inflammation and damages the cell's inheritance, DNA.

Then the OGG1 enzyme comes to the field. An enzyme is an active protein that promotes reactions in our body.

OGG1 has the task of repairing damaged DNA in our cells. This repair proves to be a kind of starter button for the immune response in our body.

It is this start button that makes the immune system hyperactive for those who have autoimmune diseases. These are diseases where the immune system starts attacking healthy cells.

The repair enzyme makes the inflammation stronger.

Previous research has shown that mice devoid of OGG1 fail to activate a strong immune response and thus obtain inflammation lighter than normal mice.

Five years ago, researcher Sintef, Torkild Visne, was interested in this enzyme when he worked at the Karolinska Institutet (KI).

He and his colleagues would develop a substance that could inhibit the repair enzyme.

He is not sure that the damage to the DNA that the enzyme is going to repair is so problematic:

– In the past, I thought ROS accidentally damaged DNA. But now it seems that these changes can not be bad at all, but, on the other hand, part of a normal immune response, "explains Visnes. But we have to investigate more about it.

This is how the molecule works. She relieves the repair enzyme to think she has already found DNA. Thus, it does not trigger a stronger inflammation. (Illustration: Sintef)
This is how the molecule works. She relieves the repair enzyme to think she has already found DNA. Thus, it does not trigger a stronger inflammation. (Illustration: Sintef)
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This is how the molecule works. She relieves the repair enzyme to think she has already found DNA. Thus, it does not trigger a stronger inflammation. (Illustration: Sintef)

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You're exaggerating my enzyme

In 2013, the research team began to hunt for an opportunity to make the OGG1 enzyme less active.

"Our idea was to look for a chemical to attach to repair proteins. This drug should be used to" defuse "the protein by cheating: Indicate the proteins that have already found the damaged DNA, thus succeeding In other words, the protein lacks the ability to initiate a hyperactive immune response.

Researcher and biochemist Torkild Visnes in the Sintef lab. (Photo by Thor Nielsen)
Researcher and biochemist Torkild Visnes in the Sintef lab. (Photo by Thor Nielsen)
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Researcher and biochemist Torkild Visnes in the Sintef lab. (Photo by Thor Nielsen)

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"We have previously worked more about measuring activity in this type of enzyme but with very intense methods of work," says Visnes.

"But by developing a method that allowed for enzymatic activity reading through fluorescence – that is, DNA repair – we could read thousands of samples in just a few hours.

After checking 18,000 possible substances for properties that could break out of his repair enzyme, the researchers went again with a drug that managed to disable OGG1. It took a year.

Further development of the molecule in the laboratory

Then a laborious process began to improve the fabric so as to obtain all the properties necessary to work in a living cell.

For a period of two years, researchers have made about a thousand small variants of the substance. Eventually they left with the young and promising TH5487, who just got his name because he came after the drug that was done before and called TH5486.

This drug has proven to have all three key properties researchers have searched for:

1. Was the OGG1 inflammatory protein so it became passive and could not bind to DNA.

2. It could also deactivate OGG1 in living cells

3. It was very stable when injected into animals.

Fresh mice in Texas

The discovery arose when researchers from the University of Texas tested the substance in mice with severe inflammation of the lungs.

TH5487 could quickly and efficiently prevent the repair enzyme from doing its job. Thus, immune cells could not detect the appearance of inflammation and were kept away from the lungs.

Therefore, pneumonia has become more sensationally better. The research team therefore believes they have found a new way of cushioning inflammation that can be used instead of or in addition to existing treatments.

The goal is to make a medicine that can work for humans. The road is long, the complicated rules and the high costs. But we have the belief that we have now found a piece that can be of great importance in treating everything from autoimmune diseases to blood poisoning, "says Visnes.

reference:

Visnes, T. et al .: The small molecule inhibitor of OGG1 suppresses the expression of proinflammatory genes and inflammation. Science. (2018) (abstract) DOI: 10.1126 / science.aar8048

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