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New class of drugs for the reversible inhibition of proteasomes
Date:11/22/2011

y. In order to modify the substance in such a way that it also works in lower concentrations such as those required for medication it was an important next step to understand how exactly the structure attacks the proteasome. To shed further light on this, the scientists conducted a crystal structure analysis. The outcome was that the hydroxyurea motif attacked the proteasome in a completely different manner than all other previously known inhibitors. It reacts via hitherto unknown binding pockets that may serve as starting points for the development of the new medication agents.

Starting from preliminary modeling studies, the researchers synthesized a series of different derivatives of the agent, which were then examined using X-ray crystallography and activity tests to optimize the effectiveness of the structure. The results showed that the proteasome inhibiting activity of the hydroxyurea derivatives depends on the two side chains attached to the basic structure.

Because the proteasome is contained in every cell and involved in numerous cellular functions the new inhibiting structure offers a whole range of applications, not only in the field of oncology. In the context of autoimmune diseases, an inhibition of the immunoproteasome, a derivative of the proteasome, might play an important role. In the case of autoimmune diseases, including some forms of rheumatism, the immune system attacks the body's own tissue. If the immunoproteasome is inhibited such over-reactions might be weakened. In future studies Professor Groll's team plans to improve the effectiveness of the hydroxyurea structure via experiments on cell cultures.


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Contact: Dr. Andreas Battenberg
battenberg@zv.tum.de
49-892-891-0510
Technische Universitaet Muenchen
Source:Eurekalert  

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