New Class of Drugs for the Reversible Inhibition of Proteasomes

Photo: Hydroxyurea derivative blocks the proteasome

The proteasome, a large protein
complex, carries out a vitally
important function in the cells of
the body. It decomposes unneeded
proteins into short pieces and
recycles them;© TUM

New medication could be developed on the basis of this previously unknown binding mechanism. The proteasome, a large protein complex, carries out a vitally important function in the cells of the body. Similar to a recycling plant, it decomposes unneeded proteins into short pieces and recycles them. In this way it controls a number of functions in the cell. It regulates cell growth and division, decomposes damaged proteins and also acts as a key partner of the immune system in immune defence and inflammatory reactions.

Due to its significant role in the growth of cancer cells, in recent years the proteasome has taken centre stage in pharmacological research as a starting point for cancer medication. When it becomes inhibited, the growth of cancer cells slows down.

Bortezomib, the first drug to apply this strategy, is used against multiple myeloma, a cancer disease of the bone marrow. Yet in spite of all its successes, the proteasome inhibitors currently in use often have severe disadvantages. As a result of their high reactivity they attack other proteins, too, thereby damaging not only cancer cells but also other healthy cells.

The search for alternatives conducted by a group of scientists headed by Professor Michael Groll has now borne fruit: In a high throughput screening, the scientists examined a substance library of 200,000 potential agents in their quest to identify proteasome inhibitors – and they were successful. They identified a new structure with the so-called N-hydroxyurea motif, which reacts not only reversibly but above all specifically with the active nucleus of the proteasome. The structure inhibits the function of particular subunits of the protein complexes, which are catalytically active, and thus incapacitates the enzyme. Because of this property, the newly discovered hydroxyurea structures work more specifically than other proteasome inhibitors and are thus expected to lead to less severe adverse side effects.

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 Groll’s team plans to improve the effectiveness of the hydroxyurea structure via experiments on cell cultures.; Source: Technische Universitaet Muenchen