Finetuning photoresponsive ligands for future therapies

Niels Hauwert, Tamara Mocking and colleagues from the Division of Medicinal Chemistry developed a new technique using photoresponsive small molecules and light to dynamically modulate the signaling properties of a complex transmembrane protein. The research has been published in the prestigious Journal of the American Chemical Society.

03/26/2018 | 1:42 PM

Photopharmacology uses photons - light -  to control the function of proteins by developing small-molecule ligands that block places on the protein where e.g. neurotransmitters should bind. With light these small-molecule ligands can either be activated or de-activated. This new technique is therefore complementary to the powerful approach of optogenetics, in which the protein itself is photoresponsive.

Hauwert and Mocking together with Maikel Wijtmans, Rob Leurs and other colleagues developed two azobenzene antagonists for an archetypical and complex GPCR (G protein-coupled receptor): the histamine H3 receptor (H3R). This receptor is present in the brain and plays an important role in cognition. Roles for this receptor in diseases such as attention disorder, Alzheimer or schizophrenia have been proposed. The two azobenzene antagonists, VUF14738 and VUF14862, can either be de-activated (VUF14862) or activated (VUF14738) with light. The activated isomer binds to H3R whereas the de-activated isomer loses substantial binding capacity. This process of photoisomerization is reversible and shows over 10-fold increased or decreased H3R binding affinities upon illumination at 360 nm.

These complementary photo-switchable ligands successfully demonstrate repeated second-scale cycles of H3R photo-modulation in a model oocyte system. The developed toolbox described in the Journal of the American Chemical Society allows modulation of the H3R receptor with very high level of temporal resolution and dynamics, and can serve as a blueprint for photo-modulation of the therapeutically highly relevant class of GPCR proteins. On the longer run, the results could contribute to a novel class of medicines that can be activated in the body with light at a particular location and time point. This very property can render drugs safer.