2. Academic Validation
  3. Structure-guided design of selective Epac1 and Epac2 agonists

Structure-guided design of selective Epac1 and Epac2 agonists

  • PLoS Biol. 2015 Jan 20;13(1):e1002038. doi: 10.1371/journal.pbio.1002038.
Frank Schwede 1,  Daniela Bertinetti 2,  Carianne N Langerijs 3,  Michael A Hadders 4,  Hans Wienk 5,  Johanne H Ellenbroek 6,  Eelco J P de Koning 7,  Johannes L Bos 8,  Friedrich W Herberg 2,  Hans-Gottfried Genieser 1,  Richard A J Janssen 3,  Holger Rehmann 8
Affiliations

Affiliations

  • 1 BIOLOG Life Science Institute, Bremen, Germany.
  • 2 Department of Biochemistry, University of Kassel, Kassel, Germany.
  • 3 Galapagos BV, CR Leiden, The Netherlands.
  • 4 Department of Chemistry, Laboratory of Crystal and Structural Chemistry, Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, The Netherlands.
  • 5 Department of Chemistry, NMR Spectroscopy, Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, The Netherlands.
  • 6 Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands.
  • 7 Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands; Hubrecht Institute/KNAW and University Medical Center Utrecht, Utrecht, The Netherlands.
  • 8 Molecular Cancer Research and Cancer Genomics Netherlands, Center for Molecular Medicine, UMC Utrecht, Utrecht, The Netherlands.
PMID: 25603503 DOI: 10.1371/journal.pbio.1002038
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.

Figures
Products