Kobauri tinkers with light
Drugs with an on/off switch
‘This is the lab where we test the molecules’, says chemist Piermichele Kobauri as we walk into a small, dark room. We’re at the top floor of the Linneausborg, but the tightly shut curtains prevent us from seeing the view of Groningen behind them. Kobauri’s research, which he’s been working on for the past few years, needs to be done in darkness.
In the corner of the room, there’s a nondescript grey device that Kobauri has been using a lot for his PhD research. He used the device to shine light on the drugs he designed himself, to see if he could switch them ‘on’ using light, an idea that his supervisors, Nobel Prize winner Ben Feringa and Wiktor Szymanski, have been working on for a long time. His research might present a solution to antibiotics resistance and drug side effects, two problems that, at first blush, don’t have anything in common.
Lock and key
Drugs like chemotherapy and antibiotics usually work pretty well to combat cancer cells or bacteria. Unfortunately, they sometimes also work a little too well in the wrong places in the body. That’s because most drugs have multiple entry points: places they can connect to certain proteins in the body. When a drug makes this connection, it’s activated.
We activate the drug locally, whenever we need it, using light
You can compare it to lock and a key: when the key fits the lock, the latter opens. However, many drugs work in both desired and undesired places in the body: the key not only fits the lock that’s meant to be fighting the disease, but other locks as well. Take chemotherapy: in an ideal world, chemotherapy would only target cancer cells, but because other organs also contain locks that fit this particular key, patients experience nasty side effects, such as hair loss or gastrointestinal issues. Antibiotics can also work in places they’re not supposed to. ‘Antibiotics also kill the good bacteria in a body, such as in the gastrointestinal tract’, says Kobauri.
The side effects are a result of the drugs killing ‘good’ cells and bacteria. This could be prevented, however, if the drugs don’t become activated until they’ve reached the right location.
And there is an added advantage to switching antibiotics on and off: it could help in the fight against antibiotics resistance. If the drug is switched ‘off’ when it ends up back in the environment, it reduces the chance of bacteria becoming resistant.
Photoswitch
Kobauri’s work focuses on drugs that are activated – and deactivated – through the use of light. These drugs have two different forms that can alternate. Embedded in their structure is what’s known as a ‘photoswitch’; a switch that can temporarily change the shape of a molecule. It can only do so when the molecule is exposed to light.
One big advantage of light is that it can be utilised with great precision. Kobauri: ‘You can easily influence light in time and space. That means you can be certain that the thing you illuminate becomes activated.’
Only one of the two forms of the drug should work in the body. ‘We can activate it locally, whenever we need it, using light.’ When the light is switched off and the medicine reverts to its previous form, the key no longer fits the lock and stops working. Just like a switch.
But how are you supposed to shine a light inside someone’s body?
Existing technique
According to Kobauri, there are several techniques to insert light into the body. One example is small LED lights that can be inserted through a small incision. Hospitals have been using this technique in photodynamic therapy, which uses light to irradiate, among other things, cancer cells, for years. ‘Because this is an existing technique, there are already tools in use to introduce light into the body.’
There are already tools in use to introduce light into the body
Another option to activate the drug is the use of light that penetrates deep into the skin. This technique is less invasive for patients, Kobauri explains. The light is able to penetrate several centimetres deep.
During his PhD research, Kobauri studied how to successfully attach a photoswitch to existing drugs. ‘You want to create as much of that on/off effect as possible’, says Kobauri, but he says there is still much room for improvement. ‘Usually, one form only binds slightly worse than the other.’ As such, right it’s not so much a matter of on/off, but rather on/a little less on.
Challenge
Another question is whether the drug still works as intended after it’s been changed. A promising idea can be a total flop in reality, which makes the development of drugs expensive and time-consuming. This goes double for drugs with a photoswitch. ‘You have to study both forms in great detail and it’s really difficult to get even one molecule approved by bodies such as the European Medicines Agency’, Kobauri explains. ‘In this case, you have to check that both are okay. That’s certainly a challenge.’
It’s difficult to get even one molecule approved
Kobauri did everything involved in the development of new drugs himself: he designed the molecules on his computer, created them in the lab – albeit with the help of his students – and made sure the molecules did what they were supposed to. It was a valuable learning experience. ‘But it was also a huge challenge to perform all the steps of the drug design process.’ For Kobauri, switching the drug on and off in the dark lab was the last step.
It would be revolutionary if we could better predict what drugs will do in a body. Not just the photowitch drugs in their two forms, but also regular drugs. Kobauri prefers the term ‘educated guesses’ rather than ‘lucky hits’ He wants to be able to substantiate and predict how a new drug will work in the body.
Algorithms
He tried to do this himself on his computer. Of all the things he’s done during his PhD research, this was his favourite. He constructed molecules with a photoswitch and used algorithms to predict what potential drugs would do. He then tested these drugs in the lab. Unfortunately, the drugs’ actions were more difficult to predict in practice, and his algorithms need optimisation.
But even though the photoswitch drugs are even harder to design than regular drugs, Kobauri has a good feeling about the future of photopharmacology. The field is still in its infancy, but people in the research field are already happy with the existence of these kinds of molecules.
At any rate, Kobauri hopes that his PhD research was able to contribute at least something to the predictability of computer-designed drugs. That would save a lot of lab work, he says, laughing, since spending all that time in the lab wasn’t really his cup of tea.