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Structure-guided design of selective Epac1 and Epac2 agonists.

ABSTRACT: The second messenger cAMP is known to augment glucose-induced insulin secretion. However, its downstream targets in pancreatic ?-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, Sp-8-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.

SUBMITTER: Schwede F

PROVIDER: S-EPMC4300089 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Structure-guided design of selective Epac1 and Epac2 agonists.

Schwede Frank F Bertinetti Daniela D Langerijs Carianne N CN Hadders Michael A MA Wienk Hans H Ellenbroek Johanne H JH de Koning Eelco J P EJ Bos Johannes L JL Herberg Friedrich W FW Genieser Hans-Gottfried HG Janssen Richard A J RA Rehmann Holger H

PLoS biology 20150120 1

The second messenger cAMP is known to augment glucose-induced insulin secretion. However, its downstream targets in pancreatic β-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 ...[more]

PMID: 25603503

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