Activate or deactivate drugs with the help of light

Scientists at the Paul Scherrer Institute PSI used the Swiss X-ray free electron laser SwissFEL and the Swiss Light Source SLS to create a film that will give a decisive boost to the development of a new class of drugs. They have made progress in the field of so-called photopharmacology, the field of developing active substances that can be specifically activated or deactivated with the aid of light.The study is published today in the journal Nature Communications.

Photopharmacology is a new medical field predicted to have a great future. It may help treat diseases such as cancer more effectively than ever before. Photopharmacological drugs are equipped with molecular photoswitches. Matter is activated by a pulse of light, but only if it reaches the area of ​​the body where it is supposed to act. And after it has done its job, it can be switched off again by another pulse of light.

This can limit potential side effects and reduce the development of drug resistance, such as to antibiotics.

Licht switch drug

A switch is incorporated to make conventional medicines sensitive to light. In their study, scientists led by lead authors Maximilian Wranik and Jörg Standfuss used the active molecule combretastatin A-4, which is currently being tested in clinical trials as an anticancer agent. It binds to a protein called tubulin, which forms the microtubules that make up the basic structure of cells in the body and promotes cell division. Combretastatin A-4, or “CA4” for short, destabilizes these microtubules, thereby suppressing the uncontrolled division of cancer cells. In other words, it slows the growth of tumors.

The modified CA4 molecule is particularly photoactive due to the addition of a bridge of two nitrogen atoms. In the inactive state, so-called azo bridges stretch the molecular components to which they are attached, forming long chains. A pulse of light bends the bonds and brings the ends of the chain closer together – like a muscle contracting to bend a joint. Importantly, in its elongated form, the molecule does not fit inside tubulin’s binding pocket — the depression on the protein’s surface where the molecule can dock to exert its effect. Fits perfectly like a key to a Such molecules that fit into corresponding binding pockets are also called ligands.

Capturing the Potential of Cancer Drugs

Recent research shows that the processes involved go far beyond the simple lock-and-key principle. It works, it’s constantly changing shape,” says Maximilian Wranik. “Whole proteins are not static.” In many cases, the binding pocket is only half-open, and the ligand stays there briefly before being released again before it can function. Alternatively, you can do a so-called “induced fit” that “fits” something that isn’t really the right shape. The ligand changes the shape of the pocket so that it can stay in place and stay there. The scientists photographed the binding site ligand changing from a bent shape to a straight shape after it was switched off, showing how the pocket adapts to this new shape before the ligand is cut off. increase. The binding pocket collapses and re-forms after some time. What is clear is that the better the ligand fits, the longer it will remain bound to the site.

In any case, a more complete understanding of these processes, visualized for the first time, opens up the possibility of designing new, more suitable active substances, improving binding times and thus drug efficacy. Improved.

A new level of structure determination

The processes involved are atomically executed within milliseconds. To observe them, the researchers used her PSI’s high-precision large-scale research facility. The combination is unmatched anywhere in the world. The Swiss Light Source SLS and the Swiss X-ray Free Electron Laser SwissFEL not only record, but individual images are of negligible time scale and small dimensions, but the entire series of images can be combined to create a movie. Project leader Jörg Standfuss said: During this period, photobiologically relevant processes take place.

Among other things, his team used SLS to analyze the structure of the molecules involved down to the atomic level, and SwissFEL to measure the process to within 100 femtoseconds (one-tenth of a trillion seconds). “Without the excellent support and cooperation of SwissFEL and his SLS experts, the realization of such a unique project would not have been possible,” he emphasizes Standfuss.

Taking active substances against gout or Covid-19

The possibility of photographing photoactive substances in action also opens the opportunity to glean many other important insights in the field of medicine.

“Of course, we also want to track the exact sequence of events when the active substance is switched on,” says Standfuss. “But this one is a little more complicated, so we won’t tackle it until the next stage.”

Separately, this study examines only one of tubulin’s many known binding pockets. Colchicine, which is used to treat gout and other inflammatory rheumatic diseases, and the new Covid 19 drug suravisabrin, still in development, also bind in the same pocket. binding sites can be examined. Standfuss hopes the method will help clinical research find more effective treatments for a variety of diseases. “With the help of our extensive research facility, we hope to open up time as a new dimension in determining the structure of active substances, allowing us to understand and further optimize them.”