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A New Discovery in the Treatment of Autoimmunity and Chronic Inflammation

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Lupus, Type 1 diabetes, and multiple sclerosis are all diseases brought on by autoimmunity — the bodies inability to tell itself apart from foreign invaders. Finding a cure, or even a suitable treatment has been to put it gently a long, painful road, with little to show for it. On the forefront of the war against the body betrayal is immunosuppressants, which with them carry their own set of side effects and in most cases only off mild to moderate relief of symptoms. But that is all changing and new research on something called immunoproteasomes offer that new hope.

The immune system functions as the body’s police force, protecting it from intruders like bacteria and viruses. However, in order to ascertain what is happening in the cell it requires information on the foreign invaders. This task is assumed by so-called immunoproteasomes. These are cylindrical protein complexes that break down the protein structures of the intruders into fragments that can be used by the defense system.

“In autoimmune disorders like rheumatism, type 1 diabetes and multiple sclerosis or severe inflammations a significantly increased immunoproteasome concentration can be measured in the cells,” explains Prof. Michael Groll. “The deactivation of this degradation machinery suppresses the regeneration of immune signaling molecules, which, in turn, prevents an excessive immune reaction.”

For some time now, scientists have been on the lookout for new active substances that block immunoproteasomes in a targeted manner without inhibiting the constitutive proteasomes also present in cells. Constitutive proteasomes break down defective or no longer required proteins and are thus responsible for cellular recycling. Notably cell death occurs, when both the constitutive proteasomes and the immunoproteasomes are inactivated. This has been a sticking point for researchers who have tried to crack the immunoproteasomes code.

In early 2012 the research team caught a break and fulfilled a prerequisite for designing specific active substances: They solved the crystal structure of the immunoproteasome, allowing them to spot the subtle but significant differences between the otherwise nearly identical structures.

The potential drug that the researchers developed is based on the epoxyketon ONX 0914, an immunoproteasome inhibitor that is undergoing clinical trials. The researchers replaced the epoxyketon with a sulfonyflouride group and modified its positioning on the inhibitor. The result was a new compound that selectively inhibits the immunoproteasome without influencing the constitutive proteasome.

“Normally inhibitors clog up the active center of the enzyme and thereby disable its functionality. The substance synthesized by us, however, attaches to its target, causing the active center to destroy itself, and then gets detached after successful inactivation,” Christian Dubiella explains.

Especially the insights into the atomic mechanisms that were uncovered using X-ray structure analysis open the door to the custom-tailored development of immunoprotease inhibitors. This may pave the road for a future generation of medications and other possible targets for specific patients.

I have to say we are on the verge of custom medicine, medications and treatments designed specifically for patients instead of the disease or illness they have. It’s a very exciting time to be around and see how it turns out. I know that there are (sadly) plenty of people that will benefit from this and other advancements in the name of autoimmune diseases.

Sources:
Dubiella C, Cui H, Gersch M, Brouwer AJ, Sieber SA, Krüger A, Liskamp RM, & Groll M (2014). Selective Inhibition of the Immunoproteasome by Ligand-Induced Crosslinking of the Active Site. Angewandte Chemie (International ed. in English) PMID: 25244435

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