Autoimmune diseases, chronic inflammations: Advancing research

Thee 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 at the TUM Department of Biochemistry. “The deactivation of this
degradation machinery suppresses the regeneration of immune signaling molecules, which, in turn,
prevents an excessive immune reaction.”

Subtle but significant differences

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.

In early 2012 the research team led by Groll 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.
Special mode of action

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.

First author Christian Dubiella explains what makes the discovered mechanism so special: “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.” 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.

Source Reference: Christian Dubiella, Haissi Cui, Malte Gersch, Arwin J. Brouwer, Stephan A. Sieber, Achim Krüger, Rob M. J. Liskamp, Michael Groll. Selective Inhibition of the Immunoproteasome by Ligand-Induced Crosslinking of the Active Site. Angewandte Chemie International Edition, 2014; DOI: 10.1002/anie.201406964

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