An international team of scientists, led by University of Texas and Karolinska Institutet researchers, has created a small anti-inflammatory molecule with a new mechanism of action.
Model of TH5487-mediated inhibition of proinflammatory gene expression: inflammation, at its onset and throughout its progress, is associated with generation of reactive oxygen species, causing damage to DNA in particular at guanine-rich promoters; OGG1 binding to oxidized guanines at promoter regions facilitates recruitment of downstream transcription factors that drive proinflammatory gene expression, and a cellular inflammatory response; in the presence of TH5487, OGG1 can no longer interact with DNA substrates in promoters, so proinflammatory gene expression is inhibited, and the cellular inflammatory response is prevented. Image credit: Visnes et al, doi: 10.1126/science.aar8048.
“We developed a new drug molecule that inhibits inflammation,” said co-lead author Professor Thomas Helleday, a researcher in the Department of Oncology-Pathology at Karolinska Institutet.
“It acts on a protein that we believe is a general mechanism for how inflammation arises in cells.”
Dubbed TH5487, the new molecule blocks the action of a key inflammation-triggering enzyme, 8-oxoguanine DNA glycosylase 1 (OGG1).
This enzyme is known to bind to sites of oxidative DNA damage and initiate DNA base excision repair.
“It turned out that OGG1, apart from repairing DNA, triggers inflammation,” Professor Helleday and colleagues said.
“TH5487 is a selective active-site inhibitor of OGG1.”
“It blocks the release of inflammatory proteins, such as TNF alpha.”
The scientists found that TH5487 was metabolically relatively stable and well tolerated in mice.
They performed a trial on mice with acute pulmonary disease and succeeded in dampening the inflammation.
“This discovery could give rise to a new treatment for a very serious condition,” Professor Helleday said.
“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 study was published in the journal Science.
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Torkild Visnes et al. 2018. Small-molecule inhibitor of OGG1 suppresses proinflammatory gene expression and inflammation. Science 362 (6416): 834-839; doi: 10.1126/science.aar8048
