The bright future of light-dependent drugs
By Helen Wright
Imagine a drug that could be turned on with the flick of a light switch. Well, this could be the future with photopharmacology, an emerging sector of modern medicine involving drugs that contain synthetic photoswitchable components to employ light-dependent pharmacological activity. It has the potential to increase the selectivity and specificity of drugs, allowing them to be targeted to highly localised parts of the body and be triggered on demand. This could limit potential side effects as the photoactive drug can be administered in its low toxicity (dark) state.
There are several ways of achieving photochemical control of a compound — some may use a photoactive ‘cage’ which masks the biologically active features of the drug, while others have a ‘photoswitch’ which on exposure to light changes conformation and activates the drug component.
The most common method is to take an established drug and synthetically modify it by incorporating one of these ‘photoswitches’, often an azo arene. Azobenzene is the simplest of these and is highly effective — low levels of light irradiation are associated with large structural changes when converting between isomers.
The impact of developments in photopharmacology could be far-reaching
A recent development in this field follows chemists at St Petersburg University. They have been working on a new phosphonate, whose biological activity can be ‘switched on’ on exposure to light. The compound is a phosphorylated arylaminomalanate that possesses both the drug and photoactive components in one, a novel advancement on the previous technologies.
It has clinical potential as a cholinesterase-inhibitor, which are often used to treat neurodegenerative conditions. Cholinesterases are enzymes that support the effective functioning of the nervous system, specifically catalysing the breakdown of acetylcholine which allows certain neurons to relax after activation. Inhibiting this breakdown is a target in treating several conditions, including dementia, as patients with Alzheimer’s disease have reduced levels of acetylcholine in the brain.
When a laser is applied to the compound, the phosphonate part turns, and this conformational change ‘switches on’ its biological activity. This response to light had not been studied before this point, and scientists noted the importance of ensuring the biological properties were altered, not just the physical form. In the compound of interest, this was “found virtually by accident, which often happens in scientific research”, says Alina Manshina, a Professor in the Department of Laser Chemistry at St Petersburg University.
Inhibiting this breakdown is a target in treating several conditions, including dementia
It is also worth noting that the structure of the compound can be slightly adapted to introduce a whole host of new characteristics. The phenyl ring of the phosphonate is a versatile site for several substituents to be added which can dramatically alter the functionality of the compound. Various elements such as fluorine, chlorine, hydrogen, or a methyl group (CH3) could be added, resulting in the agent acquiring different biological properties. Fluorine was found to enhance biological activity on light exposure the most, acting as the greatest inhibitor of cholinesterases.
The impact of developments in photopharmacology could be far-reaching; Professor Manshina commented that their discovery has the potential to “be applied in developing personalised medical solutions that consider individual characteristics of the person, choosing optimal dose and exposure”. Personalised medicine is not a new concept but has become a more viable option through the advanced understanding of the human genome in the 21st century. The coupling of this alongside photopharmacological agents could allow a new generation of highly effective and precise drug therapies.
However, at this point photopharmacology is still in the works — incredible progress has been made but logistical issues in administering light-activated drugs have come to the surface. A key issue is finding a way to irradiate the agent when inside the body as light does not penetrate tissue effectively due to absorption by biomolecules. Perhaps the light source could be implanted, and addressing these challenges opens up a huge array of in-clinic opportunities. In the words of Matthew Fuchter from Imperial College London, “the future of photopharmacology is bright!”
Illustration: Adeline Zhao
