Optical Control of Insulin Secretion Using an Incretin Switch

被引：74

作者：

Broichhagen, Johannes ^{[1
,2
]}

Podewin, Tom ^{[1
,2
]}

Meyer-Berg, Helena ^{[1
,2
]}

von Ohlen, Yorrick ^{[3
]}

Johnston, Natalie R. ^{[3
]}

Jones, Ben J. ^{[4
]}

Bloom, Stephen R. ^{[4
]}

Rutter, Guy A. ^{[3
]}

Hoffmann-Roeder, Anja ^{[1
,2
]}

Hodson, David J. ^{[3
]}

Trauner, Dirk ^{[1
,2
]}

机构：

[1] Ludwig Maximilians Univ Munchen, Dept Chem, D-81377 Munich, Germany

[2] Ctr Integrated Prot Sci CIPSM, D-81377 Munich, Germany

[3] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Dept Med, Sect Cell Biol & Funct Genom,Div Diabet Endocrino, London W12 0NN, England

[4] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Div Diabet Endocrinol & Metab, Sect Invest Med, London W12 0NN, England

来源：

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION | 2015年 / 54卷 / 51期

基金：

欧洲研究理事会; 英国生物技术与生命科学研究理事会; 英国惠康基金;

关键词：

beta cells; insulin; liraglutide; photopharmacology; type; 2; diabetes; GLUCAGON-LIKE PEPTIDE-1; BETA-CELL; RECEPTOR; BIAS;

D O I：

10.1002/anie.201506384

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

Incretin mimetics are set to become a mainstay of type 2 diabetes treatment. By acting on the pancreas and brain, they potentiate insulin secretion and induce weight loss to preserve normoglycemia. Despite this, incretin therapy has been associated with off-target effects, including nausea and gastrointestinal disturbance. A novel photoswitchable incretin mimetic based upon the specific glucagon-like peptide-1 receptor (GLP-1R) agonist liraglutide was designed, synthesized, and tested. This peptidic compound, termed LirAzo, possesses an azobenzene photoresponsive element, affording isomer-biased GLP-1R signaling as a result of differential activation of second messenger pathways in response to light. While the trans isomer primarily engages calcium influx, the cis isomer favors cAMP generation. LirAzo thus allows optical control of insulin secretion and cell survival.

引用

页码：15565 / 15569

页数：5

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