Drugs: a new approach to degrade protein

By focusing on protein degradation to make drugs with a broader field of action, researchers have succeeded in identifying genes that determine the effectiveness of these "degraders".

Everyone knows, science has its limits. Currently, drugs can target only certain protein receptors. They can only reach 20% of biological mechanisms to cure diseases. As a result, many researchers are working to try to develop new treatments with broader fields of action. For several years, they have been looking at targeted protein degradation. Thus, eventually, the new drugs could indulge in the natural activation of the degradation of problematic proteins in connection with inhibiting specific receptors. Today, according to a study published August 22 in the journal Molecular Cell, researchers have succeeded in identifying genes that determine the effectiveness of protein degraders.

According to the scientists, small molecules called "degraders" will be able to lead to the degradation of proteins by redirecting certain enzymes called ligases of our regulatory proteins to that which must be eliminated.

"We have selected a representative set of five degradation agents, which divert different ligases to degrade proteins of clinical interest." When these proteins are disrupted, ligases lose their ability to flexibly assemble and disassemble in response Instead, they begin self-labeling as part of a process called Automatic Degradation, and as a result, the degradation drugs tested fail to destabilize their target proteins and are ineffective in blocking the protein. growth of cancer cells, "says Martin Jaeger, PhD student and co-lead author of the study.

Destroy damaged proteins

This theory suggests that one could, by using certain molecules, artificially activate the system that the cell uses to search for and destroy damaged proteins, as is the case with immunotherapy.

This is the first study to completely dissect the cellular determinants of mechanically different small molecular degraders. According to the researchers, better understanding the mechanisms of resistance of cells to these "degraders" could allow to overcome them. This could notably be done thanks to advances in functional genetics, such as CRISPR scissors, and in quantitative proteomics (the study of all the proteins of a given biological sample).

"Now that the degraders enter the clinic, understanding the potential resistance mechanisms can tell us how to overcome them, the modulator gene networks we've identified can serve as biomarkers to support patient stratification, but also to learn a lot about the fundamental aspects of the regulation and the dynamics of the mechanisms of degradation of the proteins ", conclude the researchers.

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