000230565 001__ 230565
000230565 005__ 20180913064448.0
000230565 0247_ $$2doi$$a10.1002/open.201700062
000230565 022__ $$a2191-1363
000230565 02470 $$2ISI$$a000407167100010
000230565 037__ $$aARTICLE
000230565 245__ $$aPotent Prearranged Positive Allosteric Modulators of the Glucagon-like Peptide-1 Receptor
000230565 260__ $$aWeinheim$$bWiley-V C H Verlag Gmbh$$c2017
000230565 269__ $$a2017
000230565 300__ $$a5
000230565 336__ $$aJournal Articles
000230565 520__ $$aDrugs that allosterically modulate G protein-coupled receptor (GPCR) activity display higher specificity and may improve disease treatment. However, the rational design of compounds that target the allosteric site is difficult, as conformations required for receptor activation are poorly understood. Guided by photopharmacology, a set of prearranged positive allosteric modulators (PAMs) with restricted degrees of freedom was designed and tested against the glucagon-like peptide-1 receptor (GLP-1R), a GPCR involved in glucose homeostasis. Compounds incorporating a trans-stilbene comprehensively outperformed those with a cis-stilbene, as well as the benchmark BETP, as GLP-1R PAMs. We also identified major effects of ligand conformation on GLP-1R binding kinetics and signal bias. Thus, we describe a photopharmacology-directed approach for rational drug design, and introduce a new class of stilbene-containing PAM for the specific regulation of GPCR activity.
000230565 6531_ $$aallosterism
000230565 6531_ $$aBETP
000230565 6531_ $$aglucagon-like peptides
000230565 6531_ $$aglucagon-like peptide-1 receptors
000230565 6531_ $$aG protein-coupled receptors
000230565 6531_ $$astilbene
000230565 700__ $$aJones, Ben J.$$uImperial Coll London, Sect Investigat Med, Div Diabet Endocrinol & Metab, London W12 0NN, England
000230565 700__ $$aScopelliti, Rosario$$uEcole Polytech Fed Lausanne, ISIC SB, Lab Prot Engn, Av Forel 2, CH-1015 Lausanne, Switzerland
000230565 700__ $$aTomas, Alejandra$$uImperial Coll London, Sect Cell Biol & Funct Genom, Dept Med, London W12 0NN, England
000230565 700__ $$aBloom, Stephen R.$$uImperial Coll London, Sect Investigat Med, Div Diabet Endocrinol & Metab, London W12 0NN, England
000230565 700__ $$aHodson, David J.$$uUniv Birmingham, Inst Metab & Syst Res, Birmingham B15 2TT, W Midlands, England
000230565 700__ $$0249559$$aBroichhagen, Johannes$$g263631$$uEcole Polytech Fed Lausanne, ISIC SB, Lab Prot Engn, Av Forel 2, CH-1015 Lausanne, Switzerland
000230565 773__ $$j6$$k4$$q501-505$$tChemistryopen
000230565 909C0 $$0252027$$pLIP$$xU10102
000230565 909CO $$ooai:infoscience.tind.io:230565$$pSB$$particle
000230565 917Z8 $$x105423
000230565 937__ $$aEPFL-ARTICLE-230565
000230565 973__ $$aEPFL$$rREVIEWED$$sPUBLISHED
000230565 980__ $$aARTICLE