Remote control of glucose homeostasis in vivo using photopharmacology.
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.
Section of Cell Biology and Functional Genomics, Department of Medicine, Imperial College London, London, W12 0NN, UK.
Zenobia B
0000-0002-1461-5319
ZB
Mehta
Section of Cell Biology and Functional Genomics, Department of Medicine, Imperial College London, London, W12 0NN, UK.
Natalie R
NR
Johnston
Section of Cell Biology and Functional Genomics, Department of Medicine, Imperial College London, London, W12 0NN, UK.
Marie-Sophie
MS
Nguyen-Tu
Department of Chemistry and Center for Integrated Protein Science, LMU Munich, Munich, Germany.|Max-Planck Institute for Medical Research, Jahnstr. 29, 69120, Heidelberg, Germany.
Johannes
0000-0003-3084-6595
J
Broichhagen
Department of Chemistry and Center for Integrated Protein Science, LMU Munich, Munich, Germany.
Peter
P
Schultz
Institute of Metabolism and Systems Research (IMSR) and Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham, Edgbaston, B15 2TT, UK.|Centre for Endocrinology, Diabetes and Metabolism (CEDAM), Birmingham Health Partners, Birmingham, B15 2TH, UK.
Dean P
DP
Larner
Section of Cell Biology and Functional Genomics, Department of Medicine, Imperial College London, London, W12 0NN, UK.
Isabelle
I
Leclerc
Department of Chemistry and Center for Integrated Protein Science, LMU Munich, Munich, Germany. d.trauner@lmu.de.
Dirk
D
Trauner
Section of Cell Biology and Functional Genomics, Department of Medicine, Imperial College London, London, W12 0NN, UK. g.rutter@imperial.ac.uk.
Guy A
0000-0001-6360-0343
GA
Rutter
Institute of Metabolism and Systems Research (IMSR) and Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham, Edgbaston, B15 2TT, UK. d.hodson@bham.ac.uk.|Centre for Endocrinology, Diabetes and Metabolism (CEDAM), Birmingham Health Partners, Birmingham, B15 2TH, UK. d.hodson@bham.ac.uk.
David J
DJ
Hodson
D000818:Animals; D001786:Blood Glucose; D003920:Diabetes Mellitus / Q000188:drug therapy*; D064420:Drug-Related Side Effects and Adverse Reactions; D006706:Homeostasis; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D051379:Mice; D017319:Photosensitizing Agents / Q000008:administration & dosage* / Q000009:adverse effects; D013453:Sulfonylurea Compounds / Q000008:administration & dosage* / Q000009:adverse effects; D016896:Treatment Outcome
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D017319:Photosensitizing Agents; D013453:Sulfonylurea Compounds