Swedish scientists present a new way to develop drugs

A team of researchers from Karolinska Institute and the lab SciLifeLabboth in Sweden, sign a new job published in the scientific journal Science. In it, they show how they have managed to improve the function of a protein, opening the door to a new concept in drug development. The modified protein can repair oxidative damage to DNA and exert a new function. This innovative technique may lead to improvements in the discovery of treatments for diseases in which oxidative stress is part of the pathology process. That includes cancer, Alzheimer’s disease and various conditions that affect the health of the lungs, but scientists believe there could still be more applications in other fields.

To develop a new drug, pathogenic (disease-causing) proteins are traditionally sought and treatments are created that consist of blocking them with different mechanisms of action. However, many diseases are caused by a loss or decreased function of a protein, which cannot be treated by creating protein inhibitors (drugs that block proteins).

The Nobel as a starting point

In this work, researchers from the Karolinska Institute managed to improve the function of a protein called OGG1, an enzyme that repairs DNA damage caused by oxidative stress. Oxidative stress is a process that has to do with aging, but also with cancer, Alzheimer’s disease, cardiovascular and autoimmune diseases and some of the ailments that affect lung capacity.

To carry out their work, the group used a method known as organocatalysis, a tool developed by the scientists Benjamin List and David W.C. MacMillanwho received the 2021 Nobel Prize in Chemistry for this discovery.

The technique is based on the discovery that small organic molecules can serve as catalysts (increase the rate of a chemical reaction) and induce chemical reactions without becoming part of the final product.

The scientists looked at how these catalyst molecules, which had been previously described by other teams, bind to OGG1 and affect how it works in cells. One of the molecules aroused a particular interest in them, they say in a statement from the institute.

Ten times more effective

“When we use the catalyst in the enzyme, the enzyme becomes ten times more effective at repairing oxidative stress damage, and can carry out a new repair function,” he explains. Maurice Michel, associate professor in the institute’s department of oncology and pathology.

The catalyst made it possible for the enzyme to ‘cut’ the DNA in an unexpected way, so that the normal protein (APE1) is no longer needed, but another, called PNKP1.

The authors of the new work believe that the OGG1 proteins improved with this new procedure can lead to the development of new drugs for diseases in which oxidative stress has something to do with it. However, according to Thomas Helleday, professor in the same department and lead author of the study, there may be implications beyond oxidative stress. The concept of adding a small molecule as a catalyst to a protein is also used to enhance and change other proteins.

Generation of new proteins

Helleday said: “We believe this technology could drive a paradigm shift in the pharmaceutical industry by generating new functions in proteins rather than suppressing them with inhibitors. However, this technique is not limited to drugs, its applications are virtually unlimited.

The study has been funded by numerous institutions, including the European Research Council, the Swedish Research Council and the Swedish Cancer Society.