Researchers at the PSI Center for Life Sciences announced on Mar. 19 that they have observed, at the molecular level, how a light-switchable drug interacts with its biological receptor and why its potency changes. The findings were published in the journal Angewandte Chemie International Edition.
The research is significant because it advances photopharmacology, a field focused on developing drugs that can be activated or deactivated by specific wavelengths of light. This approach could allow medications to be targeted to specific areas of the body, reducing side effects by keeping them inactive elsewhere.
The team studied photoazolol-1, a beta blocker modeled after existing drugs used to treat high blood pressure and cardiac arrhythmias. Photoazolol-1 contains an azobenzene group that changes shape when exposed to violet light, making the molecule bulkier and altering how it binds to β-adrenergic receptors found in the heart and lungs. "Observing exactly what happens at such receptors when a drug is altered by light is an important step toward making light-switchable drugs a reality in the clinic," said Jörg Standfuss, laboratory head at PSI and co-author of the study.
Quentin Bertrand, one of the study's first authors and a postdoctoral researcher in Standfuss's group, explained that when photoazolol-1 is straight, it fits perfectly into certain lung receptors. After exposure to violet light, it bends but still occupies the binding pocket—though less effectively—reducing its ability to deactivate the receptor. "So we've inserted a synthetic light switch here that can alter receptor activity," Standfuss summarised. He added: "The new compound still doesn't leave the binding pocket. The molecule remains stuck and continues to block the docking site for adrenaline." Bertrand noted: "We often talk about receptors as switches... But in reality, receptors are more like regulators that can be used to amplify or weaken a process."
Previous experiments by Spanish collaborators showed that heart cells treated with photoazolol-1 could have their beating rate controlled with light exposure. The current work at SwissFEL—a large X-ray free-electron laser facility—provided atomic-level insight into these effects using time-resolved measurements.
The study also involved leadXPro, a PSI spin-off focused on developing targeted drugs through detailed investigation of membrane proteins. According to Bertrand: "Designing such molecules is often a guessing game; it's based on trial and error... Now we have shown that with SwissFEL, we can observe in detail what happens when light-switchable drugs are transformed at the receptor." The researchers plan to expand their studies to other types of receptors relevant for autoimmune reactions and neurological diseases.
Standfuss said he has been approached by several photopharmacology researchers interested in collaboration. The project was supported by funding from the Swiss National Science Foundation.
