Instantly activating or deactivating drugs at the right location is the focus of photopharmacology research. The goal is to develop drugs that can be turned on and off by specific wavelengths of light. Orally administered drugs can be selectively activated by exposing only certain parts of the body to light. The drug is no longer effective in other parts of the body, which reduces side effects. For example, a drug aimed at lowering blood pressure within the heart may only be active within the heart. Other organs that have the same binding sites as the active ingredient are not affected.
Researchers at the PSI Life Sciences Center looked at how photoswitchable drugs interact with their corresponding biological receptors at the molecular level. Most importantly, they discovered why the drug’s efficacy varies.
“Observing exactly what happens at such receptors when a drug is switched by light is an important step towards bringing light-switchable drugs to the clinic,” says Jorg Standfuss, laboratory director at the PSI Life Sciences Center and co-author of the new study published in the journal. Applied Chemistry International Edition.
switchable beta blocker
Specifically, the researchers looked at the beta-blocker photoazolol-1. The molecule is modeled after drugs that have been prescribed for decades to treat high blood pressure and arrhythmias. Photoazolol-1 exerts its effects when it binds to receptors in the body that belong to the class of so-called beta-adrenergic receptors. Such receptors are primarily found in the cell membranes of the heart and smooth muscle tissues such as the airways of the lungs. These receptors are activated by the neurotransmitters adrenaline and noradrenaline, causing typical stress responses such as increased heart rate and blood pressure. Beta-blockers, on the other hand, block these receptors and can be used to treat high blood pressure and heart problems.
Collaborative partners at the Consejo Superior de Investigaciones CentÃficas laboratory in Barcelona have developed photoazolol-1 as a molecule that can be switched using light. Compared to the version currently used in medicine, it contains an additional atomic group, the azobenzene group. “When this group is exposed to violet light, it flips around. Photoazolol-1 then has a curved section and is much larger overall,” explains Quentin Bertrand, one of the two lead authors of the new publication. He is a postdoctoral researcher in the research group of Jörg Standfuss. The conversion happens extremely fast, within picoseconds, or just a trillionth of a second.
Can be controlled, not just on and off
As PSI researchers now discover, the linear shape of photoazolol-1 fits perfectly into the binding pockets of certain receptors, primarily found in the lungs.
The light-induced bending of the molecule allows it to still fit into the binding pocket, but it binds less to the receptor and is no longer able to effectively inactivate the receptor. “So we inserted a synthetic light switch here that can change the activity of the receptor,” Jörg Standfus summarizes. What’s special: “The new compound has not yet left the binding pocket. The molecule remains attached and continues to block the adrenaline docking site.” This means that the beta blocker continues to reduce the body’s stress response, but in a passive manner rather than actively as before.
“We often talk about receptors as switches, but this means that there are only on and off versions,” says Quentin Bertrand. “But in reality, receptors are more like regulators that can be used to amplify or dampen processes.” In other words, the curved shape of beta blockers stops the regulators in a certain position, preventing them from turning any further.
However, the curved shape is also less stable and will return to its straight shape over time. For faster effects, you can expose it to green light.
cell phone cinema
The laboratory of a Spanish collaboration partner had already proven that this principle works. The researchers allowed photoazolol-1, which was equipped with a switch, to be absorbed by heart cells through a nutrient solution. By shining light on the cells, they were able to control the rate at which heart cells beat. “With our new measurements at PSI, we have discovered the atomic basis for understanding exactly why what we have observed in previous cell experiments happens,” Standfuss says.
The current study was carried out with the X-ray free electron laser SwissFEL at PSI. Only using large-scale research facilities of this kind can ultrafast molecular processes be visualized. SwissFEL’s short, intense light pulses produce something like individual frames of film, allowing time-resolved measurements.
Visionary molecular design
The study also included leadXPro, a PSI spin-off company located in Park Innovaare, right next door to PSI. The goal is to develop new targeted drugs by studying the structure and function of membrane proteins in detail.
New research provides a foundation for developing better photoswitchable drugs. “Designing molecules like this is often a guessing game and based on trial and error,” Bertrand explains. “Here, we show that SwissFEL can be used to closely observe what happens when a photo-switchable drug is converted at its receptor.” This should help in the design of new compounds.
The research team is now hoping to expand the scope of their research. The aim is to investigate other receptors and their docking partners. For example, consider photoswitchable histamine, whose receptors play a role in autoimmune reactions. Molecules that dock to adenosine receptors may also have a switch. These are, for example, binding sites for the stimulant caffeine found in coffee and for drugs used to treat Parkinson’s disease.
Jörg Standfuss has already been contacted by several photopharmacology researchers requesting collaboration. The current project is supported by a research grant from the Swiss National Science Foundation (SNSF). The future of light-activated drugs may not be far away.
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DOI: 10.1002/anie.202517995
