Psoriasis is a chronic skin disease that manifests itself mainly with skin symptoms (dryness, itching, scaly skin, abnormal spots and plaques). It affects about 2% of the population and is caused by an altered response of the immune system that triggers the proliferation of skin cells. Depending on their severity, there are different therapeutic options (topical medications, phototherapy, systemic drugs, etc.) but some conventional treatments can cause harmful effects in patients.
Now, research led by the University of Barcelona and IDIBELL confirms the therapeutic efficacy of a new compound against psoriasis that could avoid the risks associated with previously known therapies. The work reveals how a molecule activated by blue light – the compound MRS7787 – is able to modulate the activity of the immune system and treat psoriasis in an animal model.
This is a significant progress in photopharmacology research, a high-precision discipline focused on the action of compounds (photodrugs) that can be precisely activated or deactivated pharmacologically by light radiation. The work, published in the Journal of the American Chemical Society, is led by Francisco Ciruela, professor at the Faculty of Medicine and Health Sciences of the UB, leader of the Neuropharmacology and pain group at the Bellvitge Biomedical Research Institute (IDIBELL) and member of the Institute of Neurosciences (UBNeuro), and has as first author the expert Marc López-Cano. The study also includes the participation of experts Concepció Soler (UB-UBneuro-IDIBELL), Jordi Hernando (Autonomous University of Barcelona) and 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 photodrug to treat psoriasis and avoid adverse effects
The UB team has characterised the new compound MRS7787, a molecule that can be activated with light that binds to the adenosine A3 receptor – involved in several intracellular signalling pathways – and generates an anti-inflammatory effect.
The MRS7787 compound has two configurations or isomers – molecules with the same chemical formula but different structure and function – that switch with each other quickly and reversibly using light.
“The MRS7787 is a photoswitchable molecule. One of the isomers, Z-MRS7787, is inactive while the E-MRS7787 isomer activates the adenosine receptor. If we radiate with blue light, the molecule changes from the Z to E configuration, i.e. the active form. However, the green light transforms E to Z and inactivates the compound. This switching effect is achieved by the covalent binding of a photochrome called diazocine to the adenosine A3 receptor,” says Francisco Ciruela, from the Department of Pathology and Experimental Therapeutics of the UB.
“What is special about the diazocine photochrome is that it allows the photodrug MRS7787 to be in its inactive Z configuration in the dark, so that it can be injected without generating any photopharmacological response and can then be selectively activated through photoisomerization with blue light,” says Jordi Hernando, from the UAB Department of Chemistry, who has led the study of the photochemical properties of the MRS7787 compound.
The E-MRS7787 isomer is capable of selectively activating the adenosine A3 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 particular, in the approach to psoriasis,” says the expert Marc López-Cano (UB-UBneuro-IDIBELL).
As part of the study, the MRS7787 compound was administered to the animal model and for 8 minutes, a part of the body – specifically, the ears – where an inflammatory process had been induced, was irradiated with an LED device. One ear is 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 exhibit any antipsoriatic activity (unlike E-MRS7787), and this shows that the therapeutic capacity is dependent on the photoswitching of the molecule.
Combining therapies for the benefit of patients
Corticosteroids, keratolytic agents, calcineurin inhibitors, and vitamin D analogues are some of the most common topical medications used to treat mild psoriasis. The most serious cases, when there are generalized skin involvements, are treated with biological agents or chemical drugs of oral administration.
“Often these last two treatments can be combined with localized or whole-body phototherapy, which involves exposing the skin to wideband or narrow-band wavelength ultraviolet (UV) radiation. This generalized phototherapy can be supplemented with the therapy known as PUVA, which combines an oral treatment with the drug psoralen with UVA radiation. However, in the long term, this has the risk of causing skin cancer,” says the expert Marc López-Cano (UB-UBneuro-IDIBELL).
The photodrug MRS7787 opens new avenues to improve therapeutic efficacy in the multimodal treatment of psoriasis – especially refractory psoriasis – and reduce the adverse effects associated with conventional treatments.
“If we combine the MRS7787 compound with PUVA therapy, we could increase the efficacy of the treatment 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 antipsoriatic efficacy would be maintained and the patient would improve their commitment to the treatment,” the experts indicate.
MRS7787 is a molecule derived from piclidenoson, a non-photosensitive compound that also selectively binds to the adenosine A3 receptor, and is in phase 3 clinical trials to treat rheumatoid arthritis and psoriasis. Now the team also wants to validate this new pharmacological target in other inflammatory conditions – such as arthritis or pain associated with inflammatory processes – to expand their pharmacological capabilities and enhance their possible interest in other clinical areas.
The Bellvitge Biomedical Research Institute (IDIBELL) is a biomedical research center created in 2004. It is participated by the Bellvitge University Hospital and the Viladecans Hospital of the Catalan Institute of Health, the Catalan Institute of Oncology, the University of Barcelona and the City Council of L’Hospitalet de Llobregat.
IDIBELL is a member of the Campus of International Excellence of the University of Barcelona HUBc and is part of the CERCA institution of the Generalitat de Catalunya. In 2009 it became one of the first five Spanish research centers accredited as a health research institute by the Carlos III Health Institute. In addition, it is part of the “HR Excellence in Research” program of the European Union and is a member of EATRIS and REGIC. Since 2018, IDIBELL has been an Accredited Center of the AECC Scientific Foundation (FCAECC).