© GEORGE RETSECK
The desire for temporal and spatial control of medications to minimize side effects and maximize benefits has inspired the development of light-controllable drugs, or optopharmacology. Early versions of such drugs have manipulated ion channels or protein-protein interactions, “but never, to my knowledge, G protein–coupled receptors [GPCRs], which are one of the most important pharmacological targets,” says Pau Gorostiza of the Institute for Bioengineering of Catalonia, in Barcelona.
Gorostiza has taken the first step toward filling that gap, creating a photosensitive inhibitor of the metabotropic glutamate 5 (mGlu5) receptor—a GPCR expressed in neurons and implicated in a number of neurological and psychiatric disorders. The new mGlu5 inhibitor—called alloswitch-1—is based on a known mGlu receptor inhibitor, but the simple addition of a light-responsive appendage, as had been done for other photosensitive drugs, wasn’t an option. The binding site on mGlu5 is “extremely tight,” explains Gorostiza, and would not accommodate a differently shaped molecule. Instead, alloswitch-1 has an intrinsic light-responsive element.
In a human cell line, the drug was active under dim light conditions, switched off by exposure to violet light, and switched back on by green light. When Gorostiza’s team administered alloswitch-1 to tadpoles, switching between violet and green light made the animals stop and start swimming, respectively.
The fact that alloswitch-1 is constitutively active and switched off by light is not ideal, says Gorostiza. “If you are thinking of therapy, then in principle you would prefer the opposite,” an “on” switch. Indeed, tweaks are required before alloswitch-1 could be a useful drug or research tool, says Stefan Herlitze, who studies ion channels at Ruhr-Universität Bochum in Germany. But, he adds, “as a proof of principle it is great.” (Nat Chem Biol, doi:10.1038/nchembio.1612, 2014)
|TECHNIQUE||HOW IT WORKS||USE AS RESEARCH TOOL||ROAD TO CLINIC|
|Optogenetics||Particular cell types are made responsive to light by transfection with a virus encoding a light-responsive channel or receptor.||It’s ideal for studying the effects of activating a cell type in a specific location.||There are no optogenetic treatments in clinical trials, although other gene therapies are being tested in humans.|
|Optopharmacology||Ideally, light-responsive drugs given orally or intravenously would be inactive. An external or internal light source would then activate the drug.||In principle, it’s useful for studying the effects of a drug or for pharmacologically manipulating proteins, receptors, or channels to probe their normal functions.||Even if a drug is approved for clinical use, it will likely face additional scrutiny for such novel, light-guided administration.|