Tissue of retina where the new molecules have been tested (UMH)Molecular activity in an organism is linked to the three-dimensional structure of the molecule: it is the structure what allows the molecule to recognize a biological receptor and to interact with it, as a key would do in a keyhole. This coupling makes the receptor activate, which triggers the biological activity, which can be the synthesis of a protein, an enzyme or others.
Whatever the activity triggered by the receptor, if a change to the structure is achieved in a controlled way through an external stimulus, it will be possible to control its binding to the receptor. Therefore, it could be possible to obtain a molecular switch to activate or deactivate a receptor in a cell or in a living organism.
This is the goal of one of the research lines of the Biomedical Chemistry Department of the Institute of Advanced Chemistry of Catalonia (IQAC-CSIC).
The group, led by the research professor at the CSIC Amadeu Llebaria, is designing biological molecules that change their structure when they are exposed to light. The method they have developed enables a precise control of the molecular structure (from what form to what forms changes) and the wavelength of the light spectrum that makes the change possible. It allows one to choose if the change is reversible or not.
These molecules, called ‘targeted covalent photoswitches’ or TCP have many potential uses. They can be applied as drugs to re-establish the performance of receptors linked to diseases or to study the activity of the receptors. Or, in the diagnoses, to block or stimulate a process and to measure its influence on the biological answer.
It could be possible to obtain a molecular switch to activate or deactivate a receptor in a cell or in a living organism
Above all, as the most outstanding result, the scientists have obtained a chemical method that makes it possible to prepare molecules to photo-activate receptors that can be applied to many molecules. Besides, the use of super-computing and simulating tools allow one to foresee which molecular structures will be active in different cases.
Restoring the retina activity
Recently, the team obtained TCP molecules that are activated with visible light and that could replace the retina photoreceptors (rods and cones). This work was made together with scientists at the Institute for Bioengineering of Catalonia (IBEC) and other Spanish universities.
Amadeu Llebaria explains: “In normal conditions, the visual cells of the retina are triggered by the light and they activate, in their turn, other cells that will send a visual signal to the brain. The molecules we have designed are activated when they receive light: that makes them change their structure, which in turn affects their interaction with the neuronal receptors involved in the visual signalling to the brain. Our work is conceptual, a first step to demonstrate that this technique is possible, that these cells could replace the function of the rods and cones when they are damaged”.
The results, published in the Nature Communications magazine, showed that the molecules did work and that it was possible to restore the function in a damaged retina of an animal. Although restoring complete vision is not possible, scientists say it could help to recover sensitivity to light.
Uses for the central nervous system
The scientists are also designing molecules that modulate the activity in the glutamate receptors. Recent results of this work have been published in the Cell Chemical Biology magazine, in an article led by Amadeu Llebaria, at the IQAC-CSIC, Pau Gorostiza, at the IBEC, and Cyril Goudet, at the Functional Genomic Institute of the CNRS (France).
Glutamate receptors are involved in the synaptic transmissions of the central nervous system. They are involved in many processes, such as pain perception, memory or motor regulation. Also, the impairment of their activity is associated to some disorders. Therefore they are interesting targets for potential therapies.
In this case, the scientists have managed to increase or reduce the activity of the glutamate receptor with a molecule that changes its structure when it receives violet light.
The molecules could be used for biological studies of the central nervous system, or to assess new therapies. Also, explains Amadeu Llebaria, it could be applied as drugs that act locally in a brain zone, activating them with implantable ‘micro-leds’. The work is still in the “conceptual proof’ stage, as scientists try to determine if this strategy could be real or not.
These molecules could open the door to personalized and improved therapies. Besides, this type of treatments could bring very localized treatments, with a control of the place where the drug is applied as well as the duration of their effects, like the ones proposed in the new ‘precision medicine’ approach.
Reference articles:
Xavier Rovira et al., (2016) OptoGluNAM4.1, a Photoswitchable Allosteric Antagonist for Real-Time Control of mGlu4 Receptor Activity, Cell Chemical Biology, http://dx.doi.org/10.1016/j.chembiol.2016.06.013
M. Izquierdo-Serra et al. (2016). Optical control of endogenous receptors and cellular excitability using targeted covalent photoswitches. Nature Communications, doi:10.1038/ncomms12221