A study with the involvement of the UAB presents a new efficient photopharmaceutical drug to treat psoriasis and reduce the adverse effects associated with conventional treatments.
Psoriasis is a chronic skin disease that manifests itself mainly with skin symptoms (dryness, itching, scaly skin, abnormal patches and plaques). It affects about 2% of the population and is mediated by an altered immune system response that triggers the proliferation of skin cells. Depending on the severity, there are different therapeutic options available (topical medications, phototherapy, systemic drugs, etc.), but some conventional treatments can have harmful effects on patients.
Now, a study by the University of Barcelona (UB) and the UAB confirms the therapeutic efficiency of a new compound against psoriasis, which could avoid the risks associated with previously known therapies. The study reveals how a molecule activated by blue light — the MRS7787 compound — can modulate the activity of the immune system and treat psoriasis in an animal model.
This is a major advance in photopharmacology research, a high-precision discipline focused on the action of compounds (photopharmaceuticals) that can be precisely activated or deactivated pharmacologically by light irradiation.
The study, published in the Journal of the American Chemical Society, is led by Francisco Ciruela, professor at the UB's Faculty of Medicine and Health Sciences and member of the Institute of Neurosciences (UBNeuro) and the Bellvitge Biomedical Research Institute (IDIBELL), with expert Marc López-Cano as first author. The paper also highlights the involvement of experts Concepció Soler (UB, UBneuro and IDIBELL) and Jordi Hernando (Universitat Autònoma de Barcelona), as well as the teams of Kenneth Jacobson, from the National Institutes of Health (NIH) in Bethesda, and Dirk Trauner, from the University of Pennsylvania (United States).
A photopharmaceutical drug to treat psoriasis and avoid adverse effects
The researchers have characterized the new MRS7787 compound, a light-activatable molecule that binds to the A3 adenosine receptor — involved in several intracellular signalling pathways — and generates an anti-inflammatory effect.
The MRS7787 compound has two configurations or two isomers — molecules with the same chemical formula but different structure and function — that are rapidly and reversibly switched by light.
Francisco Ciruela, professor at the UB's Faculty of Medicine and Health Sciences who has lead the research, notes that "MRS7787 is a photo-switchable molecule. One of the isomers, Z-MRS7787, is inactive, while the E-MRS7787 isomer activates the adenosine receptor". He goes on to say, "When irradiated with blue light, the molecule changes from the Z to the E configuration, i.e. the active form. However, green light transforms E into Z and inactivates the compound". "This switching effect is achieved by the covalent binding of a photochrome called diazocine to the A3 adenosine receptor", continues Francisco Ciruela, who is also researcher in the UB's Department of Pathology and Experimental Therapeutics.
"What is special about the diazocine photochrome is that it allows the photopharmaceutical MRS7787 to be in its inactive Z-configuration in the dark so that it can be injected without generating any photopharmacological response, and then selectively activated by photoisomerisation with blue light," says Jordi Hernando, from the Department of Chemistry at the Universitat Autònoma de Barcelona, who led the study of the photochemical properties of the MRS7787 compound.
The E-MRS7787 isomer can selectively activate the A3 adenosine receptor without affecting the signalling of the other adenosine receptors. "This activation has an anti-inflammatory effect and reduces the production of pro-inflammatory cytokines by immune system cells. Therefore, activating this receptor is an effective strategy to treat inflammatory processes in general, and in the approach to psoriasis in particular", says expert Marc López-Cano (UB, UBneuro and IDIBELL).
As part of the study, the animal model was administered the MRS7787 compound and, for eight minutes, a part of the body — namely the ears — where an inflammatory process had been induced was irradiated with an LED device: one ear was irradiated with blue light of 1.18 mW/cm2 intensity, and the other ear with green light of 7.64 mW/cm2 intensity. The results indicate that the Z-MRS7787 isomer — the result of irradiating the molecule with green light — did not show any anti-psoriatic activity (unlike E-MRS7787), demonstrating that the therapeutic capacity is dependent on the photoswitching of the molecule.
Combining therapies for patients
Corticosteroids, keratolytic agents, calcineurin inhibitors and vitamin D analogues are some of the most common topical medications used to treat mild psoriasis. More severe cases, where there is widespread skin involvement, are treated with biologics or orally administered chemical drugs.
"Often the latter two treatments can be combined with localized or whole-body phototherapy, which involves exposing the skin to ultraviolet (UV) radiation of broad- or narrowband wavelength. This generalized phototherapy can be complemented by the therapy known as PUVA, which combines an oral treatment with the drug psoralen with UVA irradiation. However, in the long term this has the risk of causing skin cancer", says López-Cano.
The photopharmaceutical MRS7787 opens new avenues to improve therapeutic efficiency in the multimodal treatment of psoriasis — especially treatment-resistant psoriasis — and to reduce the adverse effects associated with conventional treatments. "If we combine the MRS7787 compound with PUVA therapy, we could increase treatment efficiency and reduce adverse effects (skin cancer, etc.). The use of multimodal phototherapy could simplify the treatment regimen, as the dosage of light irradiation would be adjusted once a day, the anti-psoriatic efficiency would be maintained and patient engagement with treatment would be improved", the experts say.
MRS7787 is a piclidenoson-derived molecule, a non-photosensitive compound that also selectively binds to the A3 adenosine receptor, which is in a phase 3 clinical trial to treat rheumatoid arthritis and psoriasis. The team now also wants to validate this new drug target in other inflammatory conditions — such as arthritis or pain associated with inflammatory processes — to broaden its pharmacological capabilities and enhance its potential interest in other clinical settings.
Reference article:
López-Cano, Marc; Scortichini, Mirko et al. "Photoswitchable diazocine derivative for adenosine A3 receptor activation in Ppsoriasis". Journal of the American Chemical Society, December 2024. DOI: 10.1021/jacs.4c13558.
