Are you aware of non-steroidal anti-inflammatories, the so-called NSAIDs? We use them often, to relieve pain and inflammation, as well as to lower fever. These drugs have a very specific mechanism of action: they block particular enzymes, cyclooxygenases (COX) 1 and 2, which enter into the production of prostaglandins which perform various functions. These molecules, in addition to mediating the inflammatory response, also help protect the gastric mucosa and regulate blood flow. Therefore, if specific COXs are not selectively inhibited, healthy tissues can also be affected, with consequent unwanted effects.
To respond to this need, the so-called “Photocoxibs” are being developed, i.e. molecules that change structure under the action of light and once “turned on” can more precisely inhibit only COX-2, which comes into play precisely in possible unwanted effects. Italian research is also participating in this effort to make drugs even more targeted.
An international study
An international research coordinated by the State University of Milan with the groups of Carlo Matera and Giovanni Grazioso, both professors of Pharmaceutical Chemistry of the Department of Pharmaceutical Sciences, and Anna Pistocchi, professor of Cellular and Applied Biology of the Department of Medical Biotechnology and Translational Medicine, was dedicated to working on these “Photocoxibs”.
The study saw the participation of the group of Antonietta Rossi, professor of Pharmacology and Pharmacovigilance of the Department of Pharmacy of the University of Naples Federico II, with the contribution of the post-doc Danilo D’Avino, together with the Universitat Autònoma de Barcelona and the Institute for Bioengineering of Catalonia and was published in the Journal of the American Chemical Society.
In particular, the study led to the development of new versions of celecoxib, an anti-inflammatory which belongs to the selective inhibitors of COX-2, an enzyme involved in inflammatory processes.
In search of light
Unlike traditional drugs, these new molecules, the “Photocoxibs”, work like switches: they change structure when they are illuminated and, in the “turned on” form, show greater effectiveness in selectively inhibiting COX-2. In this way it is possible to modulate the therapeutic effect of the drug in space and time, activating it only where and when needed, without also affecting healthy tissues and therefore causing sometimes important side effects, such as gastric or cardiovascular problems. In the absence of light, the molecule returns to its starting shape, allowing reversible control of the activity.
After a computational design phase, the researchers synthesized three molecules in the laboratory and verified their response to light. A particularly important result emerged in tests on macrophages, immune cells responsible for removing pathogens and damaged material: after light activation, the compounds showed an inhibitory activity towards COX‑2 up to five times higher than their non-illuminated form. The most promising candidate, photocoxib-6 (PC6), was then tested in an acute inflammation model in zebrafish. In this experiment, the light-activated form of the compound reduced the arrival of leukocytes in the lesion area, a key signal of the inflammatory response.
What are coxibs
Coxibs were developed because they were able to achieve a selective inhibition of cyclooxygenase 2: through this route they proved capable of reducing inflammatory processes and at the same time promoting analgesia. Not only that: precisely because they respect COX-1 they allow the potential damage of NSAIDs in long-term treatments on the stomach mucosa to be reduced.
