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Heart therapies: scientists have succesfully designed and tested beta blockers controlled by light

A research tested in zebrafish shows the potential of photopharmacology for future heart therapies more precise and with fewer side effects. The study is published in the journal Angewandte Chemie International Edition, selected as a Hot Paper.

Scientists have designed drugs for the treatment of heart pathologies that are activated and controlled by lightResearchers at the Institute of Advanced Chemistry of Catalonia (IQAC), in collaboration with the Institute of Environmental Diagnosis and Water Studies (IDAEA), have developed molecules that allow the activity of beta-adrenergic receptors located in cardiomyocytes, cells of the heart muscle, to be controlled by light.

The research, published in the journal Angewandte Chemie International Edition and tested in zebrafish models, shows the potential of photopharmacology (drugs activated and controlled by light) for the study and control of cardiac physiology, and its applicability in living beings. The results of this work point to the generation of future therapies that are more precise and have fewer adverse effects.

Adrenergic receptors, located on the surface of cells, are activated by substances called catecholamines (adrenaline and noradrenaline). Their regulation is essential for the correct functioning of the heart and many other physiological processes. One of these receptors is the so-called β-adrenergic receptor, which is found in heart, arteries and lungs. Catecholamines stimulate these receptors, therefore increasing heart rate and bronchodilation, among other effects.

These receptors are the main target of beta-blocker drugs, which are among the most prescribed drugs worldwide and are used to treat various cardiac conditions, such as heart rhythm disorders and cardioprotection after myocardial infarction. These drugs block the β-adrenergic receptor, thereby preventing the binding of catecholamines and preventing their stimulation, and improving heart function.

However, some patients with respiratory problems may suffer adverse effects derived of the beta-blocker drugs. These unwanted effects can be avoided if the drug only acts in the desired place (the heart) and only when is strictly necessary. This is the aim of photopharmacology.

High precision in site and time of action

In this study, scientists have designed and produced several photoregulable molecules with beta-blocker activity. "This work presents a new strategy for high-precision control of the β1-adrenergic receptor using photosensitive molecules," explains Xavier Rovira, a researcher in the Medicinal Chemistry group at IQAC.

"One of the advantages offered by photopharmaceuticals is that they make it possible to focus therapeutic action in specifics space and time. This could modulate the physiology of the organism in a way that simulates its normal functioning, improving the efficiency and safety of treatments," explains the researcher Anna Duran, first author of the article, who did her doctoral thesis at the IQAC.

This work demonstrates that these photoregulable molecules can increase and decrease the heart rate by using light of different colours

This work demonstrates that these photoregulable molecules, which have a similar potency and selectivity to approved beta-blockers, can increase and decrease the heart rate by using light of different colours. These molecules were tested in in vitro assays, and in live zebrafish larvae. "This study confirms the enormous potential of zebrafish as a vertebrate model for cardiac photopharmacology studies," says Demetrio Raldúa, a researcher in the Environmental Toxicology group at the IDAEA.

This is the first proof of concept of the potential of photopharmacology for the study and control of cardiac physiology in native environments without the need of genetic modification, where the β1-adrenergic plays a fundamental role. Such molecules could meet the conventional procedures and drug requirements developed by pharmaceutical companies.

The future: possible scenarios

But how can photopharmaceuticals be activated by light in inner parts of the body such as the heart or other internal organs? Researchers envision implantable microsystems, microleds, that would allow precise control of the localised release of a drug, as well as the amount of light needed to activate it. They could be implanted in an organ or in subcutaneous tissue. Such devices are currently under development in international bioengineering laboratories.

For example, in the future, a patient with a heart condition could wear a sensor bracelet that monitors his or her vital signs. The patient could be taking a daily medication of photopharmaceuticals that will produce no effect as long as it is not activated by light.

"Then, when the patient has a cardiac crisis, a microled (smaller than the head of a pin) would irradiate the appropriate area with light to activate the medication, while sending a medical report to the hospital. The microled could be installed in a very specific region of the heart and would be activated automatically when the sensor detects an anomaly in the patient's heart rate," explains Xavier Rovira.

"In the future, molecules with different light-controlled capabilities will be developed for future research applications. We hope than our research and other similar works will inspire the development of treatments for heart diseases that are much more efficient and have fewer adverse effects" concludes Rovira.

Reference article :

Anna Duran-Corbera, Melissa Faria, Yuanyuan Ma, Eva Prats, André Dias, Juanlo Catena, Karen L. Martinez, Demetrio Raldua, Amadeu Llebaria, Xavier Rovira. A Photoswitchable Ligand Targering the β1-Adrenoceptor Enables Light-Control of the Cardiac Rhythm. Angewandte Chemie. Int. Ed. DOI: 10.1002/anie.202203449