Research sheds light on innovative techniques to improve drugs for diseases

In a paper that was just published in Science, scientists from Sweden’s Karolinska Institutet and SciLifeLab explain how they were able to enhance a protein’s capacity to repair oxidative DNA damage while also giving the protein a new role. The researchers’ ground-breaking method may result in better treatments for oxidative stress-related diseases including cancer, Alzheimer’s disease, and lung conditions, but researchers think it has much more promise.

Finding particular pathogenic proteins and developing medicines that include inhibiting them in different ways have long been the foundation of drug research. The loss or reduction in protein function, which many diseases result from, cannot be directly targeted by inhibitors.

Based on a Nobel Prize-winning discovery

The OGG1 protein, an enzyme that fixes oxidative DNA damage and is linked to aging and diseases including Alzheimer’s disease, cancer, obesity, cardiovascular diseases, autoimmune disorders, and lung diseases, was enhanced in the present study by researchers from the Karolinska Institutet.

The team employed an approach known as organocatalysis, a device created by Benjamin List and David W.C. MacMillan, who was honored with the 2021 Nobel Prize in Chemistry. The technique is predicated on the finding that tiny organic molecules may function as catalysts and initiate chemical processes without becoming a component of the result.

The scientists investigated how such catalyst molecules, which had already been reported by others, attach to OGG1 and impact how it performs in cells. Among the molecules, one was found to be especially interesting.

Ten times more effective

When we introduce the catalyst into the enzyme, the enzyme becomes ten times more effective at repairing oxidative DNA damage and can perform a new repair function.”

Maurice Michel, Study First Author and Assistant Professor, Department of Oncology-Pathology, Karolinska Institutet

The catalyst allowed the enzyme to alter the way it normally cuts DNA so that it no longer needs the protein APE1 to function and can instead use the protein PNKP1.

Scientists think that by altering OGG1 proteins in this way, new treatments for conditions where oxidative damage is involved may result. However, the study’s final author, Professor Thomas Helleday of the Department of Oncology-Pathology at the Karolinska Institutet, sees more extensive uses for the idea of incorporating a tiny catalyst molecule into a protein, including the enhancement and modification of other proteins.

New protein functions are generated

We believe that this technology could instigate a paradigm shift in the pharmaceutical industry, whereby new protein functions are generated instead of being suppressed by inhibitors. But the technique isn’t limited to drugs. The applications are virtually unlimited.”

Thomas Helleday, Study Final Author and Professor, Department of Oncology-Pathology, Karolinska Institutet

Source:
Journal reference:

Michel, M., et al. (2022) Small-molecule activation of OGG1 increases oxidative DNA damage repair by gaining a new function. Science. doi.org/10.1126/science.abf8980.

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