AIMMS researchers discover photocontrol of G protein-coupled receptor activation

Medicinal Chemists Xavi Gómez-Santacana, Sabrina de Munnik and colleagues have discovered a series of molecules for which the efficacy in activating an important receptor protein can be regulated with light.

07/19/2018 | 4:13 PM

The research, led by Maikel Wijtmans, Henry Vischer and Rob Leurs, has been published in the prestigious Angewandte Chemie International Edition

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Photoswitchable molecules

In general, the efficacy of a ligand is determined by its action upon binding to its target protein receptor: either the ligand just blocks the receptor (antagonism) or it induces receptor-mediated intracellular signaling (agonism).

Photopharmacology is a contemporary research area that capitalizes on light to direct biological properties, affording so-called photoswitchable molecules. However, most focus in the field has been on photomodulating the binding affinity of a ligand for its receptor. Indeed, in work published earlier this year in the Journal of the American Chemical Society the VU team had also reported a case study focused on bidirectional photomodulation of binding affinity for a hallmark example for the G protein-coupled receptor (GPCR) family, the histamine H3 receptor.

Ligand efficacy

In the current research work, the team took the concept a step further by photomodulation of ligand efficacy and did so on a more challenging peptidergic GPCR, the CXCR3 receptor. Perturbed signaling by this chemokine receptor is thought to be involved in various diseases including cancer.

The molecules of Gómez-Santacana, de Munnik and colleagues contain an azobenzene photoswitchable unit positioned near a so-called activation hotspot that was previously discovered by the VU team. The best molecule (VUF16216) could reversibly photoswitch from a CXCR3 antagonist to a full agonist, either blocking or maximally activating CXCR3, respectively. The observed magnitude of the photoswitching in efficacy is unprecedented in the GPCR photopharmacology field.

Not only does this work add a highly useful tool compound for CXCR3 research, but it also demonstrates how tailored molecular design can enable real-time photocontrol over the efficacy of GPCR-binding molecules, which itself can be a blueprint for advancing novel types of medicines for this therapeutically highly relevant protein class.