The future for research into a key biological complex is a lot brighter thanks to researchers in the Netherlands. Herman Overkleeft and colleagues at Leiden University have developed a series of new inhibitors for the proteasome, a human protein complex, simply by swapping parts of well-known inhibitors.

The proteasome has many functions, one of which is to break down proteins into peptides. These peptides can interfere with the immune system, and so inhibiting the proteasome could find application in treating auto-immune diseases, such as type I diabetes. 

Overkleeft and his colleagues have developed a panel of proteasome inhibitors by scrambling the structural elements of the best-known peptide-based examples. Each combined an 'electrophilic trap' (to bind to the protein complex) with a peptide sequence (to mimic the proteasome's natural substrates). Edward Tate, a chemical geneticist at Imperial College London, UK, suggested that 'the inhibitors represent the first in a new generation of powerful chemical tools to probe specific and multiple activities of the proteasome.' 

One of the new inhibitors proved to be 'one of the most potent proteasome inhibitors reported to date,' said Overkleeft. It contains a boronic ester as the trap, similar to a group present in the drug bortezomib, which is used to re-sensitise cancers of the immune system to chemotherapy. The other half of the molecule is a tetrapeptide sequence from the natural product epoxomicin, a known proteasome inhibitor.

Overkleeft said that the challenge now lies in assessing how good the inhibitors are at inhibiting specific functions of the proteasome, and then developing better inhibitors using different traps and peptides. This should lead to a 'better understanding of the proteasome as a drug target, and maybe also to the development of new therapeutics,' said Overkleeft.

David Barden