Using light to switch drugs on and off

Scientists at the Paul Scherrer Institute PSI have used the Swiss X-ray free-electron laser SwissFEL and the Swiss Light Source SLS to make a film that could give a decisive boost to developing a new type of drug. They made the advance in the field of so-called photopharmacology, a discipline that develops active substances which can be specifically activated or deactivated with the help of light. The study is being published today in the journal Nature Communications.

Photopharmacology is a new field of medicine that is predicted to have a great future. It could help to treat diseases such as cancer even more effectively than before. Photopharmacological drugs are fitted with a molecular photoswitch. The substance is activated by a pulse of light, but only once it has reached the region of the body where it is meant to act. And after it has done its job, it can be switched off again by another pulse of light.

This could limit potential side effects and reduce the development of drug resistance – to antibiotics, for example.

Licht-switchable drugs

To make conventional drugs sensitive to light, a switch is built into them. In their study, the scientists led by the principal authors Maximilian Wranik and Jörg Standfuss used the active molecule combretastatin A-4, which is currently being tested in clinical trials as an anti-cancer drug. It binds to a protein called tubulin, which forms the microtubules that make up the basic structure of the cells in the body, and also drive cell division. Combretastatin A-4, or “CA4” for short, destabilises these microtubules, thereby curbing the uncontrolled division of cancer cells, i.e. it slows down the growth of tumours.

In the modified CA4 molecule, a bridge consisting of two nitrogen atoms is added, which makes it particularly photoactive. In the inactive state, the so-called azo bridge stretches the molecular components to which it is attached to form an elongated chain. The pulse of light bends the bond, bringing the ends of the chain closer together – like a muscle contracting to bend a joint. Crucially, in its elongated form, the molecule does not fit inside the binding pockets of the tubulin – depressions on the surface of the protein where the molecule can dock in order to exert its effect. However, when the molecule is bent, it fits perfectly – like a key in a lock. Molecules like this, which fit into corresponding binding pockets, are also called ligands.

Read more on the PSI website

Image: Jörg Standfuss (left) and Maximilian Wranik in front of the experimental station Alvra of the Swiss X-ray free-electron laser SwissFEL, where the photopharmacological studies were carried out. In the long term, the aim is to develop drugs that can be switched on and off by light.

Credit: Paul Scherrer Institute/Markus Fischer