Abstract
Photopharmacology describes the use of light to precisely deliver drug activity in space and time. Such approaches promise to improve drug specificity by reducing off-target effects. As a proof-of-concept, we have subjected the fourth generation photoswitchable sulfonylurea JB253 to comprehensive toxicology assessment, including mutagenicity and maximum/repeated tolerated dose studies, as well as in vivo testing in rodents. Here, we show that JB253 is well-tolerated with minimal mutagenicity and can be used to optically-control glucose homeostasis in anesthetized mice following delivery of blue light to the pancreas. These studies provide the first demonstration that photopharmacology may one day be applicable to the light-guided treatment of type 2 diabetes and other metabolic disease states in vivo in humans.
Highlights
The production of drugs with improved safety profiles remains of paramount importance to ensure healthy aging across lifespan
In response to dark and light, JB253 adopts its trans- and cis- isomer, respectively (Fig. 1b). This allows the reversible blockade of KATP channels in pancreatic beta cells, leading to increases in Ca2+ conductance and Ca2+-dependent exocytosis of insulin granules[9, 10]
The new synthetic route did not alter photoswitching properties, since reversible optical control could be afforded over Ca2+ fluxes in intact islets of Langerhans treated with bulk-produced JB253 (Fig. 1d and e)
Summary
The production of drugs with improved safety profiles remains of paramount importance to ensure healthy aging across lifespan. This can impact disease management, especially for chronic diseases such as type 2 diabetes (T2D) where the aim is to maintain normal glucose homeostasis for long periods with as few side effects as possible To this end, sulfonylureas have been used for the treatment of T2D for the past half century, since they bind the SUR1 subunit of the ATP-sensitive potassium (KATP) channel to potently induce insulin release[2,3,4]. JB253 and JB558 are fourth generation or so-called “photoswitchable” sulfonylureas (IUPHAR/BPS ligand id: 7787) Such photopharmacological approaches allow drug activity to be targeted using light[11, 12]. Correspondence and requests for materials should be addressed to www.nature.com/scientificreports/
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