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.
"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."
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.
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," says Professor Helleday. "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."
The discovery was made in collaboration with Professor Istvan Boldogh from the University of Texas Medical Branch, USA.
The repair pathway on which OGG1 operates was discovered by Tomas Lindahl at Karolinska Institutet in the 1970s, an achievement that earned him the Nobel Prize in Chemistry in 2015.
The study was a collaboration between Karolinska Institutet, Uppsala University and Stockholm University in Sweden and the University of Texas Medical Branch, USA.
It was financed by grants from 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).
Some of the authors, including Thomas Helleday, are listed as inventors on a US patent application for OGG1 inhibitors. The patent is owned by the Helleday Foundation, of which Thomas Helleday and co-author and KI researcher Ulrika Warpman Berglund are board members and through which they are involved in the development of OGG1 inhibitors for clinical application.
Publication: "Small-molecule inhibitor of OGG1 suppresses pro-inflammatory gene expression and inflammation". Torkild Visnes, Armando Cázares-Körner, Wenjing Hao, Olov Wallner, Geoffrey Masuyer, Olga Loseva, Oliver Mortusewicz, Elise?e Wiita, Antonio Sarno, Aleksandr Manoilov, Juan Astorga-Wells, Ann-Sofie Jemth, Lang Pan3, 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 and Thomas Helleday. Science, online 15 November 2018.