A multidisciplinary team of researchers led from Karolinska Institutet in Sweden have developed an anti-inflammatory drug molecule with a new mechanism of action. By inhibiting a certain protein, the researchers were able to reduce the signals that trigger an inflammation. The study is published in Science and was done in collaboration with the University of Texas Medical Branch, Uppsala University and Stockholm University. The discovery is the result of many years of research by Thomas Helleday’s group about the DNA repair in the body. One of the objectives has been to fight cancer by targeting damage to the tumor cells’ DNA. Several breakthroughs have already been reported, which have led, amongst other things, to a new treatment for congenital breast and ovarian cancer using so-called PARP inhibitors, which has been available for some years. It was when developing a new molecule for inhibiting the enzyme that repairs oxygen damage to DNA that the researchers found, to their surprise, that it also dampened inflammation.
It turned out that the enzyme OGG1, apart from repairing DNA, also triggers inflammation. The inhibitor blocks the release of inflammatory proteins, such as TNF-alpha. In trials on mice with acute pulmonary disease, the researchers succeeded in dampening the inflammation. The mechanism how the OGG1 enzyme regulates such phenomenon is not yet elucidated. This enzyme looks like it turned out to be a so called “moonlightning” protein. Moonlighting proteins comprise a class of multifunctional proteins in which a single polypeptide chain performs multiple physiologically relevant biochemical or biophysical functions. Moonlighting proteins are expressed throughout the evolutionary tree and function in many different biochemical pathways. Some moonlighting proteins can perform both functions simultaneously, but for others the protein’s function changes in response to changes in the environment. An example is the human mitochondrial enzyme aconitase, which is a key protein in both energy production and a “sensor” for iron metabolism alterations.
Since OGG1, along with the MTH1 oncogene, are involved in hereditary colorectal cancer, it might explain partially the link between chronic gut inflammation seen in inflammatory bowel diseases and the predisposition to colon cancers. Besides, the TNF-alpha is a cytokine actively involved in the pathogenesis of inflammatory gut diseases, like Crohn’s disease, or in lung diseases like chronic obstructive bronchitis (COPD). But scientists would not easily expect to come across a surprise like this. “We’ve developed a new drug molecule that inhibits inflammation,” says Professor Thomas Helleday, at the Department of Oncology-Pathology, Karolinska Institutet, Sweden, who co-led the study with Dr. Torkild Visnes and Dr. Armando Cázares-Körner. “It acts on a protein that we believe is a general mechanism for how inflammation arises in cells. This discovery could give rise to a new treatment for a very serious condition. We’ll now be developing our OGG1 inhibitor and examining whether it can lead to new treatments for inflammatory diseases in order to cure or relieve diseases such as sepsis, COPD and severe asthma”.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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