DNA Binding As An Anti-inflammatory

An anti-inflammatory drug molecule with a new mechanism of action has been developed by a team led by Karolinska Institutet researchers . By inhibiting a certain protein, the researchers were able to reduce the signals that trigger an inflammation.

“We’ve developed a new drug molecule that inhibits inflammation. It acts on a protein that we believe is a general mechanism for how inflammation arises in cells,”

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. The work was done in collaboration with the University of Texas Medical Branch, Uppsala University and Stockholm University.

PARP Inhibitors

The discovery is the result of many years of research by Thomas Helleday’s group on how DNA is repaired by the body. One of the objectives has been to fight cancer by targeting damage to the tumour 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.

Targeting Inflammatory Diseases

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.

“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,

says Professor Helleday.

The research was supported by Vinnova, the Knut and Alice Wallenberg Foundation, the Swedish Foundation for Strategic Research, the Swedish Research Council, the Swedish Cancer Society, the Swedish Childhood Cancer Foundation, the Swedish Pain Relief Foundation, the Torsten Söderberg Foundation, the National Institute of Allergic and Infectious Diseases (USA), the faculty of medicine and healthcare science at the Norwegian University of Science and Technology (NTNU), the Central Norway Regional Health Authority and the Svanhild and Arne Must Fund for Medical Research (Norway).

Torkild Visnes, Armando Cázares-Körner, Wenjing Hao, Olov Wallner, Geoffrey Masuyer, Olga Loseva, Oliver Mortusewicz, Elisée Wiita, Antonio Sarno, Aleksandr Manoilov, Juan Astorga-Wells, Ann-Sofie Jemth, Lang Pan, Kumar Sanjiv, Stella Karsten, Camilla Gokturk, Maurice Grube, Evert J. Homan, Bishoy M. F. Hanna, Cynthia B. J. Paulin, Therese Pham, Azita Rasti, Ulrika Warpman Berglund, Catharina von Nicolai, Carlos Benitez-Buelga, Tobias Koolmeister, Dag Ivanic, Petar Iliev, Martin Scobie, Hans E. Krokan, Pawel Baranczewski, Per Artursson, Mikael Altun, Annika Jenmalm Jensen, Christina Kalderén, Xueqing Ba, Roman A. Zubarev, Pål Stenmark, Istvan Boldogh, Thomas Helleday
Small-molecule inhibitor of OGG1 suppresses proinflammatory gene expression and inflammation
Science 16 Nov 2018: Vol. 362, Issue 6416, pp. 834-839 DOI: 10.1126/science.aar8048

Image: Thermal Vision Research, Wellcome Collection. CC BY