In Vivo Photopharmacology

Abstract

Synthetic photoswitches have been known for many years, but their usefulness in biology, pharmacology, and medicine has only recently been systematically explored. Over the past decade photopharmacology has grown into a vibrant field. As the photophysical, pharmacodynamic, and pharmacokinetic properties of photoswitches, such as azobenzenes, have become established, they have been applied to a wide range of biological targets. These include transmembrane proteins (ion channels, transporters, G protein-coupled receptors, receptor-linked enzymes), soluble proteins (kinases, proteases, factors involved in epigenetic regulation), lipid membranes, and nucleic acids. In this review, we provide an overview of photopharmacology using synthetic switches that have been applied in vivo, i.e., in living cells and organisms. We discuss the scope and limitations of this approach to study biological function and the challenges it faces in translational medicine. The relationships between synthetic photoswitches, natural chromophores used in optogenetics, and caged ligands are addressed.

Hemithioindigos for Cellular Photopharmacology: Desymmetrised Molecular Switch Scaffolds Enabling Design Control over the Isomer‐Dependency of Potent Antimitotic Bioactivity

“…Two main approaches have been used to deliver isomerically dependent changes of protein affinity in “narrow” photopharmacology: 1) The photoswitch is directly appended onto a druglike pharmacophore with the aim that isomerisation impacts the steric access of the pharmacophore to its binding partner, which in the context of azobenzenes is called “azo‐extension”; 2) The photoswitch is embedded entirely inside the most critical part of the pharmacophore, which in the context of azobenzenes is called “azologization” . As far as possible, embedding approaches would seem the more rational design, and have been shown to deliver significant differences between the potencies of the more‐ and less‐bioactive isomers (“photoswitchability of bioactivity”) in a variety of cellular and organism‐based settings …”

Binding and Beyond: What Else Can G‐Quadruplex Ligands Do?

“…In these cases, the activity of the ligand is unlocked in response to a stimulus, such as photoirradiation or the redox environment . Such approaches allow an additional level of spatiotemporal control over the system, and therefore potential to act as starting points for a new generation of smart drugs where activity can be controlled with greater precision to minimize off‐target side effects , . In Sections 3 and 4 we aim to provide a snapshot of progress in these exciting areas of G4 ligand development.…”

Axitinib: A Photoswitchable Approved Tyrosine Kinase Inhibitor

“…Controlling the biological activity of proteins, such as cellular enzymes or receptors, by targeted irradiation with light is a fascinating and promising approach in photopharmacology and chemical biology . In general, photoresponsive compounds can be used to translate the focused effect of the external stimulus, “light,” into biological systems.…”

“…In general, photoresponsive compounds can be used to translate the focused effect of the external stimulus, “light,” into biological systems. Such photochromic compounds can be designed as molecular switches that are either covalently linked to biomolecules or act as photosensitive ligands/modulators of the desired protein . Photoswitchable ligands are powerful tools to investigate and elucidate complex biological systems because they enable precise spatial and temporal control of the targeted protein from outside (biorthogonal).…”