Photoswitchable Molecular Tools: Applications to Enzymes, GPCRs and Ion Channels

Photocontrolled molecular tools provide powerful means to manipulate and interrogate biological functions with high spatiotemporal precision and low invasiveness. Our research efforts in the field have focused on the design of reversible photoswitchable compounds to photocontrol enzymes, GPCRs, and ion channels. Among others, we have developed phototrexate, the first photoswitchable inhibitor of the human dihydrofolate reductase with demonstrated cytotoxicity in vitro and in zebrafish larvae,1 and PAI, a light-controlled dualsteric agonist of muscarinic M2 receptors that enabled photomodulation of cardiac function in tadpoles and brain states in mice.2 More recently, we have designed a fast photoswitchable tethered ligand of ionotropic glutamate receptors to enable activation of the auditory neurons with light. This compound, named TCPfast, induced photocurrents in untransfected neurons upon covalently tethering to endogenous glutamate receptors and activating them reversibly with blue light. We applied it to the ultrafast synapses of cochlear auditory neurons that encode sound and provide auditory input to the brain. TCPfast functions as a molecular prosthesis that bypasses the neurotransmitter-encoded signal with a photonic signal. Photosensitization of cochlear spiral ganglion neurons (SGNs) by locally administered TCPfast enabled temporally precise light-evoked firing up to a rate of approximately 1 kHz, matching the fastest optogenetic SGN stimulation.3 Hence, TCPfast shows that photopharmacology might serve as an interesting alternative for the development of optical cochlear implants for hearing restoration. The main results of all these studies will be presented and discussed. References 1. Matera C et al. Journal of the American Chemical Society 2018, 140 (46), 15764–15773. 2. Riefolo F, Matera C et al. Journal of the American Chemical Society 2019, 141 (18), 7628–7636. 3. Garrido-Charles A, Huet A, Matera C et al., Journal of the American Chemical Society 2022, 144 (21), 9229–9239.