Researchers in IBEC’s Nanoprobes and Nanoswitches group and their collaborators have announced the development of the first ever light-controlled therapeutic agent whose effects focus specifically on the largest, most important class of drug target proteins – G protein-coupled receptors.
In the journal Nature Chemical Biology this week, the scientists reveal Alloswitch-1, the latest advance in their research into photoswitchable (or light-operated) drugs. Controlling drug activity with light means that the therapeutic effects can be accurately delivered locally, thus reducing their effect on other areas and the resultant side effects, and helps reduce the dosage required.
Above: Alloswitch-1 is the first light-controlled allosteric modulator of a G protein–coupled receptor. It is selective for the metabotropic glutamate receptor mGlu5 and enables
the optical control of mGlu5 signaling in vivo.
The colleagues, from IBEC, IQAC-CSIC, UAB and IDIBELL in Barcelona and the IGF-CNRS in Montpellier in France, developed the small molecule therapeutic agent that modulates drug target protein receptors specifically at the allosteric, or non-active, site of the protein. Allosteric modulators have a number of advantages over traditional drugs, offering higher selectivity of target receptors, tunable release according to whether the undesirable protein receptor activity is present, and lower potential for toxic effects.
“To build a photocontrolled modulator of a G protein-coupled receptor, we had to develop a new chemical design concept in which the photoswitch is not tethered to the drug but inserted within the pharmacophore, which is the group of atoms in the molecule of a drug responsible for its action,” explains Pau Gorostiza, group leader of IBEC’s Nanoprobes and Nanoswitches group. “We also got a bit lucky, because we not only obtained a photoswitchable GPCR ligand, but one of the most potent and selective allosteric modulators in its class.”
The effects of this ‘optopharmacological’ compound can be remotely controlled in space and time in living, wild-type organisms. This is an advantage over optogenetic manipulations, which require gene overexpression using viruses, for example.
Small molecule therapeutic agents as Alloswitch-1, if they can be made available orally, could offer a competitive advantage over traditional drugs, which often affect off-target tissues and organs, leading to unwanted consequences and compromising their beneficial effects.
Reference article: Silvia Pittolo, Xavier Gómez-Santacana, Kay Eckelt, Xavier Rovira, James Dalton, Cyril Goudet, Jean-Philippe Pin, Artur Llobet, Jesús Giraldo, Amadeu Llebaria & Pau Gorostiza (2014). An allosteric modulator to control endogenous G protein-coupled receptors with light.. Nature Chemical Biology, 10, 813–815