Jörg Standfuss (left) and Quentin Bertrand are two of the researchers in the PSI Center for Life Sciences who now have found out, on the molecular level, why a light-controllable drug changes its potency.
Photo Credit: © Paul Scherrer Institute PSI/Markus Fischer
Scientific Frontline: Extended "At a Glance" Summary: Blood Pressure-Lowering Drug with a Light Switch
The Core Concept: Researchers have developed and observed a light-switchable blood pressure medication that alters its molecular shape and potency when exposed to specific wavelengths of light. This advancement allows the drug's therapeutic effects to be modulated with precise timing and localization within the body.
Key Distinction/Mechanism: Unlike standard beta blockers, the experimental drug photoazolol-1 contains an integrated azobenzene atomic group functioning as a synthetic light switch. When irradiated with violet light, this atomic group flips, changing the molecule from a straight to a bulkier, bent shape. While the molecule remains inside the binding pocket of the β-adrenergic receptor, its altered form binds less effectively, reducing its capacity to block adrenaline and dynamically altering the receptor's activity.
Origin/History: The switchable molecule was synthesized by collaboration partners at the Consejo Superior de Investigaciones Científicas in Barcelona. Its exact molecular transformation mechanisms were subsequently mapped by researchers at the Paul Scherrer Institute (PSI) using the SwissFEL X-ray free-electron laser, with the findings recently published in the journal Angewandte Chemie.
Major Frameworks/Components:
- Photopharmacology: The core discipline focused on developing pharmaceuticals that can be toggled on or off using specific wavelengths of light.
- β-Adrenergic Receptors: Cellular membrane targets, located primarily in the heart and smooth muscle tissues, which the drug binds to in order to regulate stress responses.
- Azobenzene Photoswitch: A light-sensitive atomic functional group engineered into the drug to induce controlled conformational changes.
- Molecular Imaging: The use of advanced X-ray technology (SwissFEL) to observe ultra-fast, dynamic drug-receptor interactions at the atomic level.
Branch of Science: Photopharmacology, Structural Biology, Biochemistry, and Pharmacology.
Future Application: This research provides the foundation for orally administered drugs that remain inert throughout the body until activated by light at a highly specific anatomical site, drastically reducing systemic side effects. Future development aims to expand to other receptors, including the design of light-switchable histamines for the localized treatment of autoimmune reactions.
Why It Matters: The ability to precisely control when and where a drug acts inside the body represents a major leap forward for targeted therapies. By localizing drug activation, clinicians can maximize therapeutic efficacy at the target site while avoiding adverse side effects in surrounding healthy tissues.
Rendering a drug effective or ineffective in a flash at the appropriate location – this is the focus of research in photopharmacology. The goal is to develop drugs that can be switched on and off with light of a specific wavelength. Orally administered medications could then be selectively activated by irradiating only a specific part of the body with light; the medication would remain ineffective in the rest of the body – thus reducing side-effects. For example, a drug intended to lower blood pressure in the heart could then be activated only there; other organs with identical binding sites for the active ingredient would remain unaffected.
Researchers in the PSI Center for Life Sciences have now observed, at the molecular level, how a light-switchable drug interacts with its corresponding biological receptor. Most importantly, they have discovered why the drug changes its potency.
“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,” says Jörg Standfuss, a laboratory head in the PSI Center for Life Sciences and co-author of the new study published in the journal Angewandte Chemie International Edition.
Switchable beta blocker
Specifically, the researchers observed the beta blocker photoazolol-1. This molecule is modelled after a drug that has been prescribed for decades to treat high blood pressure and cardiac arrhythmias. Photoazolol-1 exerts its effect when it binds to a receptor in the body belonging to the class of so-called β-adrenergic receptors. Such receptors are in the cell membrane, primarily in the heart and in smooth muscle tissue, for example in the airways of the lungs. These receptors are activated by the neurotransmitters adrenaline and noradrenaline, triggering typical stress responses such as increased heart rate and blood pressure. Beta blockers, on the other hand, inhibit these receptors and therefore can be used to treat high blood pressure and heart problems.
Collaboration partners from the Consejo Superior de Investigaciones Científicas research institute in Barcelona 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, an azobenzene group. “This atomic group flips when irradiated with violet light. Photoazolol-1 then has a bent section and becomes much bulkier overall,” explains Quentin Bertrand, one of the two first-authors of the new publication. He is a postdoctoral researcher in Jörg Standfuss’s research group. The transformation occurs lightning-fast, within picoseconds – that is, in just trillionths of a second.
Controllable, not just on and off
As the PSI researchers have now discovered, the straight shape of photoazolol-1 fits perfectly into the binding pocket of a specific receptor that is found primarily in the lungs.
When triggered by light, the molecule changes to its bent shape; it still fits into the binding pocket but binds less effectively to the receptor, so it can no longer deactivate it efficiently. “So, we’ve inserted a synthetic light switch here that can alter receptor activity,” Jörg Standfuss summarizes. What’s special about it: “The new compound still doesn’t leave the binding pocket. The molecule remains stuck and continues to block the docking site for adrenaline.” This means that the beta blocker continues to reduce the body’s stress responses, though more in a passive way than actively as before.
“We often talk about receptors as switches, which implies that there are only on and off versions,” Quentin Bertrand says. “But in reality, receptors are more like regulators that can be used to amplify or weaken a process.” In other words: The beta blocker’s curved shape stops the regulator in a specific position, so it can’t be turned any farther.
However, the curved shape is also less stable and reverts back to its straight shape over time. For a faster effect, it can be exposed to green light.
Cellular cinema
In the laboratory of the Spanish cooperation partners, the principle had already been proven to work: The researchers had allowed heart cells to absorb photoazolol-1, equipped with a switch, via a nutrient solution; when they subsequently irradiated the cells with light, they could control how fast the heart cells beat. “With our new measurements at PSI, we have now found the atomic basis for understanding exactly why what was observed in previous cell experiments occurs,” says Standfuss.
The current investigations were carried out at the X-ray free-electron laser SwissFEL at PSI. Only with this type of large research facility can the ultrafast molecular processes be visualized. The short, intense light pulses of SwissFEL generate something like the individual frames of a film and thus allow time-resolved measurements.
Molecular design with foresight
The study also involved leadXPro, a PSI spin-off located in Park Innovaare right next to PSI. Its goal is to develop new and targeted drugs by investigating the structure and function of membrane proteins in detail.
The new study provides the foundation for developing better light-switchable drugs. “Designing such molecules is often a guessing game; it’s based on trial and error,” Bertrand explains. “Now we have shown that with SwissFEL, we can observe in detail what happens when light-switchable drugs are transformed at the receptor.” This should aid in the design of new compounds.
The team now wants to broaden the scope of their research: The aim is to examine other receptors and their docking partners. For example, a light-switchable histamine, whose receptor plays a role in autoimmune reactions, would be conceivable. Molecules that dock onto adenosine receptors could also be equipped with a switch. These are, for example, docking sites for the stimulating caffeine in coffee or for medicinal agents used to treat Parkinson’s disease.
Jörg Standfuss has already been approached by several photopharmacology researchers who would like to collaborate with him.The future of light-activated drugs may not be so far off.
Funding: The current project is supported by a research grant from the Swiss National Science Foundation (SNSF).
Published in journal: Angewandte Chemie International Edition
Title: Structural Mechanism of an Efficacy Photoswitch Targeting the β2-adrenergic Receptor
Authors: Robin Stipp, Quentin Bertrand, Matilde Trabuco, Anna Duran-Corbera, Maria Tindara Ignazzitto, Hannah Glover, Fabienne Stierli, Juanlo Catena, Melissa Carrillo, Sina Hartmann, Hans-Peter Seidel, Matthias Mulder, Thomas Mason, Yasushi Kondo, Maximillian Wranik, Martin Appleby, Christoph Sager, Raymond Sierra, Gregory Gate, Pamela Schleissner, Xinxin Cheng, Tobias Weinert, Robert Cheng, Sandra Mous, John H. Beale, Michal Kepa, Amadeu Llebaria, Michael Hennig, Xavier Rovira, and Joerg Standfuss
Source/Credit: Paul Scherrer Institute | Brigitte Osterath
Reference Number: phar031926_01
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