Proteins such as Ras and Myc, known to be culpable in human cancer, and Huntingtin, which causes Huntingdon’s disease, have proved stubbornly resistant to efforts to find ways of tackling them with drugs.
Now researchers at the University of Dundee, led by Professor Alessio Ciulli, have found a way of targeting similar proteins, using a small-molecule approach in an unconventional way to target “bad proteins” by binding them to neutralising agents to start a process of degradation, and thereby removing them entirely.
“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,” said Professor Ciulli.
“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.
“Research in our lab in the past few years has contributed towards establishing a different approach, one that has been theorised for many years but which is only now fully realised by this latest work. Instead of using the small molecule to try and disable the bad protein, we have developed a way of modifying it so that it can be used to attract the neutralising proteins, which then bind to their bad neighbour and act against it, starting a cascade process of degradation.
“Crucially, we have also found that it is not enough for this neutralising protein to sit close to the bad protein, it has to make direct contact with it, to `kiss’ it. And not just a little peck, but a real `Gone With The Wind’ embrace. We call this a ‘kiss of death’, as it is the key to ensure the degradation of the bad protein.”
Professor Ciulli and colleagues focused their attention on a bivalent chemical degrading molecule called `PROTAC’ (Proteolysis-targeting chimeric molecules).
They have been able to create the first X-ray crystal structure of a PROTAC bound to both the ‘bad’ protein and the ‘neutralising’ agent (an E3 ubiquitin ligase), and found that it can successfully be deployed as a `magnet’ to draw the two target proteins together.
“This discovery provides the first ever insights into how PROTACs work and how we can target proteins for degradation in a highly selective manner,” said Professor Ciulli.
“This presents a paradigm shift in how we can ensure selective chemical intervention against proteins which we know are factors in causing disease but which until now have been impossible to successfully target. It points towards the possibility of drugging the undruggable.”
The results of the research are published in the journal Nature Chemical Biology.