All cells in the human body share the same genes. But how our genes are expressed determines whether a cell becomes a brain cell or a liver cell. In addition, changes in gene expression often play an important role in disease development.
One mechanism that contributes to changes in gene expression is the interaction between proteins called histones and enzymes known as HDACs. These enzymes help the cell divide and develop, which is why they serve as targets for anti-cancer medicine: When you inhibit the enzymes, the cancer cells will stop dividing and grow further.
Although they are targets for clinically approved drugs, researchers do not know every detail of how they work in the cell. Now, researchers from the University of Copenhagen have developed a method that helps change that.
We’ve shown details about how these enzymes interact with the proteins around our DNA, and our method provides a new way to identify potential anticancer drugs very quickly. In the study, we showed that the method works: We created a peptide that affects only the right parts of living human cells, using the same target that anti-cancer medicine uses today, says Carlos Moreno Yruela, a postdoctoral researcher in the Department of Drug Design and Pharmacology.
The unmodified peptide had an effect
HDACs are a group of eleven different enzymes, which means that targeting them all at once with a non-selective drug will affect many essential processes in the body. This may also explain some of the side effects in the clinically approved HDAC-blocking anti-cancer drugs.
“Our detailed insight into the interactions of acquired enzymes with the new method provides hope for developing more specific HDAC inhibitors with potential as drug candidates. This could hold promise for developing more complex cancer treatment compounds with fewer side effects,” says Professor Christian Adam Olsen.
In the study, researchers used the new method to identify peptides, which they reproduced in larger quantities and exposed to human cells. The results were exactly as they had hoped: the expected HDACs were also inhibited in live cells.
We were surprised to see such a prominent effect of a non-enhanced peptide in cells. Usually, one needs to introduce a variety of modifications to improve its properties. But this peptide, almost completely natural, had a really powerful effect, confirming the potential of our findings, ”says Christian Adam Olsen.
The researchers now hope to use a method to identify promising candidate drugs that could be continued in preclinical testing.
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