Structure-guided design of selective Epac1 and Epac2 agonists

Frank Schwede; Daniela Bertinetti; Carianne N Langerijs; Michael A Hadders; Hans Wienk; Johanne H Ellenbroek; Eelco J P de Koning; Johannes L Bos; Friedrich W Herberg; Hans-Gottfried Genieser; Richard A J Janssen; Holger Rehmann

doi:10.1371/journal.pbio.1002038

Structure-guided design of selective Epac1 and Epac2 agonists

Frank Schwede, Daniela Bertinetti, Carianne N Langerijs, Michael A Hadders, Hans Wienk, Johanne H Ellenbroek, Eelco J P de Koning, Johannes L Bos, Friedrich W Herberg, Hans-Gottfried Genieser, Richard A J Janssen, Holger Rehmann

Hubrecht Institute

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

62 Citations (Scopus)

Abstract

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 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.

Original language	English
Pages (from-to)	e1002038
Journal	PLoS Biology
Volume	13
Issue number	1
DOIs	https://doi.org/10.1371/journal.pbio.1002038
Publication status	Published - Jan 2015

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abstract = "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 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.",

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AU - Schwede, Frank

AU - Bertinetti, Daniela

AU - Langerijs, Carianne N

AU - Hadders, Michael A

AU - Wienk, Hans

AU - Ellenbroek, Johanne H

AU - de Koning, Eelco J P

AU - Bos, Johannes L

AU - Herberg, Friedrich W

AU - Genieser, Hans-Gottfried

AU - Janssen, Richard A J

AU - Rehmann, Holger

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Structure-guided design of selective Epac1 and Epac2 agonists

Abstract

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