Structure-Guided Design of Selective Epac1 and Epac2 Agonists

被引：67

作者：

Schwede, Frank ^{[1
]}

Bertinetti, Daniela ^{[2
]}

Langerijs, Carianne N. ^{[3
]}

Hadders, Michael A. ^{[4
]}

Wienk, Hans ^{[5
]}

Ellenbroek, Johanne H. ^{[6
]}

de Koning, Eelco J. P. ^{[6
,7
,8
]}

Bos, Johannes L. ^{[9
]}

Herberg, Friedrich W. ^{[2
]}

Genieser, Hans-Gottfried ^{[1
]}

Janssen, Richard A. J. ^{[3
]}

Rehmann, Holger ^{[9
]}

机构：

[1] BIOLOG Life Sci Inst, Bremen, Germany

[2] Univ Kassel, Dept Biochem, D-34125 Kassel, Germany

[3] Galapagos BV, Cr Leiden, Netherlands

[4] Univ Utrecht, Dept Chem, Lab Crystal & Struct Chem, Bijvoet Ctr Biomol Res, NL-3584 CH Utrecht, Netherlands

[5] Univ Utrecht, Dept Chem, NMR Spect, Bijvoet Ctr Biomol Res, NL-3584 CH Utrecht, Netherlands

[6] Leiden Univ, Med Ctr, Dept Nephrol, Leiden, Netherlands

[7] Hubrecht Inst KNAW, Utrecht, Netherlands

[8] Univ Med Ctr Utrecht, Utrecht, Netherlands

[9] UMC Utrecht, Ctr Mol Med, Mol Canc Res & Canc Genom Netherlands, Utrecht, Netherlands

来源：

PLOS BIOLOGY | 2015年 / 13卷 / 01期

关键词：

DEPENDENT PROTEIN-KINASE; PANCREATIC BETA-CELLS; CA2+-INDUCED CA2+ RELEASE; CAMP-BINDING DOMAINS; EXCHANGE FACTOR EPAC; CYCLIC-AMP ANALOG; INSULIN-SECRETION; B-CELLS; UNPROTECTED NUCLEOSIDES; SULFONYLUREA RECEPTOR;

D O I：

10.1371/journal.pbio.1002038

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The second messenger cAMP is known to augment glucose-induced insulin secretion. However, its downstream targets in pancreatic beta-cells have not been unequivocally determined. Therefore, we designed cAMP analogues by a structure-guided approach that act as Epac2-selective agonists both in vitro and in vivo. These analogues activate Epac2 about two orders of magnitude more potently than cAMP. The high potency arises from increased affinity as well as increased maximal activation. Crystallographic studies demonstrate that this is due to unique interactions. At least one of the Epac2-specific agonists, Sp8- BnT-cAMPS (S-220), enhances glucose-induced insulin secretion in human pancreatic cells. Selective targeting of Epac2 is thus proven possible and may be an option in diabetes treatment.

引用

页数：26

共 66 条

[1] A meta-analysis of serious adverse events reported with exenatide and liraglutide: Acute pancreatitis and cancer [J].