Researchers at the Institute for Bioengineering of Catalonia (IBEC) based at PCB, the Institute of Advanced Chemistry of Catalonia (IQAC-CSIC) and the Institute of Functional Genomics of Lyon (IGFL) have developed molecules that can modulate the activity of glutamate receptors in the central nervous system, with important applications in biomedicine.

For the last few years the collaborators have been working on the development of molecules called targeted covalent photoswitches (TCPs), whose structure can be changed using light. This change in shape causes the molecule to be recognized – or not – by a biological receptor as a key is to a lock. This coupling activates the receptor or not, triggering the activity.

The study –recently published in the journal Cell Chemical Biology and led by Pau Gorostiza, ICREA scientist at IBEC, Amadeu Llebaria of IQAC-CSIC, and Cyril Goudet of the Functional Genomics Institute IGFL–introduces new molecules of this kind. In this case, the scientists have made a molecule that changes shape on receiving a violet light and attaches to glutamate receptors, which causes the latter to increase or decrease their activity. The controlled use of light allows for accurate and localized coupling.

Glutamate receptors are involved in synaptic transmission in the central nervous system. They are involved in many processes, such as pain perception, memory, and motor regulation. An alteration in their activity is associated with several diseases, so being able to control them is an important approach for drug development.

In a commentary on the article in the same journal, Ferdinando Nicoletti, a leading expert on glutamate receptors, highlights the importance and novelty of the research. He talks about the potential of research into photoactivated compounds for drugs for diseases such as Parkinson’s, and their possible application in treatments for localized pain.

The molecules could also be used for biological studies of the central nervous system or to assess new therapies, as Amadeu Llebaria explains. They can be thought of as controlled drugs that act in a certain area of the brain activated by ‘micro-LEDs’ implanted in the body. The study is still in the proof of concept phase, attempting to show whether or not this strategy is possible.

These molecules could open the door to personalized treatment of diseases through improved prior diagnosis and custom tailoring of drugs. In addition, the use of such drugs could lead to precise control at the relevant site and controling the duration of their effects, in line with the new move towards precision medicine.

The work also involved scientists from the Autonomous University of Barcelona (UAB) and the Center for Biomedical Research (CIBER-BNN) network.
 

•Reference article: Xavier Rovira, Ana Trapero, Silvia Pittolo, Charleine Zussy, Adèle Faucherre, Chris Jopling, Jesús Giraldo, Jean-Philippe Pin, Pau Gorostiza, Cyril Goudet, Amadeu Llebaria. OptoGluNAM4.1, a Photoswitchable Allosteric Antagonist for Real-Time Control of mGlu4 Receptor Activity. Cell Chemical Biology, Volume 23, Issue 8, 18 August 2016, Pages 929-934.