Photoswitching the Efficacy of a Small‐Molecule Ligand for a Peptidergic GPCR: from Antagonism to Agonism

Abstract

Foroptical control of GPCR function, we set out to develop small-molecule ligands with photoswitchable efficacy in which both configurations bind the target protein but exert distinct pharmacological effects,that is,stimulate or antagonize GPCR activation. Our design was based on ap reviously identified efficacy hotspot for the peptidergic chemokine receptor CXCR3 and resulted in the synthesis and characterization of five new azobenzene-containing CXCR3 ligands.G protein activation assays and real-time electrophysiology experiments demonstrated photoswitching from antagonism to partial agonism and even to full agonism (compound VUF16216). SAR evaluation suggests that the size and electron-donating properties of the substituents on the inner aromatic ring are important for the efficacy photoswitching. These compounds are the first GPCR azoligands with anearly full efficacy photoswitch and may become valuable pharmacological tools for the optical control of peptidergic GPCR signaling.

Easily Accessible, Highly Potent, Photocontrolled Modulators of Bacterial Communication

“…This showcases one of the first examples of the photopharmacological approach with opposing activities (inhibitor versus activator) of the different isomers. 23 Next, we applied AHL5 to P. aeruginosa (PA14 DlasI) to control toxin production (pyocyanin) with light. Pyocyanin production is under direct QS control, making it an interesting target to confirm the applicability of our approach in vitro.…”

“…Incorporation of photoswitches into the pharmacophore renders the product reversibly photoresponsive. Applying the photopharmacological approach, a variety of biological targets and tools ranging from ion channels, [18][19][20] glutamate receptors, 21,22 and G-protein-coupled receptors 23 to antibiotics [24][25][26] and…”

Transient Photoinactivation of Cell Membrane Protein Activity without Genetic Modification by Molecular Hyperthermia

“…Current approaches include optogenetics, 1,2 chromophore-assisted light inactivation (CALI), 3,4 and synthetic photoswitches. 5,6 Optogenetics uses light to control cell activity, especially in neurons that have been genetically modified to express photosensitive proteins. Over the past decade, this technique has been instrumental in our understanding on how specific cell types contribute to brain activity and neurological diseases.…”

Computational Investigation of Protein Photoinactivation by Molecular Hyperthermia

“…Using light to selectively and remotely control biological functions of living systems is a long-pursed objective in biomedical science [1]. Various approaches have been developed during the last decade, such as optogenetics [2] and synthetic photoswitches [3,4]. Optogenetics utilizes photosensitive molecules to genetically modify the protein of interest and enables light manipulation of targeted cells.…”