Scientists use kiss of death to neutralize disease-causing proteins

A team at the university used a technique, called a kiss of death, which forces molecules to bind to proteins such as Ras and Myc. 

Led by Professor Alessio Ciulli in Dundee’s School of Life Sciences, the researchers have discovered a way wherein they degrade and eliminate the disease-causing proteins by targeting them with similar proteins through a small-molecule approach.

Using the unconventional method, the “bad” proteins are targeted and bound with neutralizing agents.

Ciulli said: “We know of many proteins which are active in causing diseases, but which we have been unable to block from going `rogue’ or to stop them when they do.

“The major problem is that we have been unable to find the small molecules which can successfully bind to these proteins and at the same time hamper their function. It is a highly complex area – these proteins can often fool regulators within the cell and be extremely difficult to pin down with inhibitors.”

According to Ciulli, the neutralizing protein has to make direct contact forcibly with the bad protein to ensure the latter’s degradation.

In connection with this, the scientists focused on `PROTAC’ (Proteolysis-targeting chimeric molecules), a bivalent chemical degrading molecule.

An X-ray crystal structure of the binding by PROTAC of the bad protein and the neutralizing agent, E3 ubiquitin ligase was created which demonstrated that the molecules could be successfully used as magnet to bring together the two target proteins.

The Dundee scientists paired BRD4, a BET bromodomain protein which is a potential drug target for cancer, with MZ1, a selective BRD4 degrader. It was found that MZ1 could bind the two proteins successfully and eventually forcing the bad one to degrade.

Ciulli concluded that the discovery shows how PROTACs work in selectively targeting the bad proteins and forcing them to degrade.