Structural Aspects of Photopharmacology: Insight into the Binding of Photoswitchable and Photocaged Inhibitors to the Glutamate Transporter Homologue

Abstract

Photopharmacology addresses the challenge of drug selectivity and side effects through creation of photoresponsive molecules activated with light with high spatiotemporal precision. This is achieved through incorporation of molecular photoswitches and photocages into the pharmacophore. However, the structural basis for the light-induced modulation of inhibitory potency in general is still missing, which poses a major design challenge for this emerging field of research. Here we solved crystal structures of the glutamate transporter homologue Glt Tk in complex with photoresponsive transport inhibitorsazobenzene derivative of TBOA (both in trans and cis configuration) and with the photocaged compound ONB-hydroxyaspartate. The essential role of glutamate transporters in the functioning of the central nervous system renders them potential therapeutic targets in the treatment of neurodegenerative diseases. The obtained structures provide a clear structural insight into the origins of photocontrol in photopharmacology and lay the foundation for application of photocontrolled ligands to study the transporter dynamics by using time-resolved X-ray crystallography.Article pubs.acs.org/JACS

Photopharmacology of Ion Channels through the Light of the Computational Microscope

“…Recent advancements in membrane protein structural biology, in particular cryo-EM, have substantially increased the number of available ion channel and receptor structures [ 128 , 129 ] that can be used as input to design photoswitchable ligands. In this regard, a recent study has reported crystal structures of the glutamate transporter homologue Glt Tk in complex with a photoswitchable inhibitor in either cis or trans form [ 129 ]. In addition, these new experimental structures have broadened the range of templates available to build homology models for other ion channels without experimental structures.…”

Biocatalytic enantioselective hydroaminations enabling synthesis of N-arylalkyl-substituted l-aspartic acids

“…Examples of important L-aspartate derivatives include biodegradable metal chelators, metallobeta-lactamase and glutamate transporter inhibitors, photoswitchable and photocaged drug-like molecules, as well as various N-heterocycles and other chiral synthons that are widely used in pharmaceutical synthesis. [19][20][21] We have recently initiated structure-based and computer-aided protein engineering studies with the aim to enlarge the electrophile substrate scope of EDDS lyase to further increase its synthetic usefulness.…”

A Photosensitive Polymeric Carrier with a Renewable Singlet Oxygen Reservoir Regulated by Two NIR Beams for Enhanced Antitumor Phototherapy

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