title: 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 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.
authors.affiliation: BIOLOG Life Science Institute, Bremen, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Schwede
authors.affiliation: Department of Biochemistry, University of Kassel, Kassel, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Bertinetti
authors.affiliation: Galapagos BV, CR Leiden, The Netherlands.
authors.forename: Carianne N
authors.initials: CN
authors.lastname: Langerijs
authors.affiliation: Department of Chemistry, Laboratory of Crystal and Structural Chemistry, Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, The Netherlands.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Hadders
authors.affiliation: Department of Chemistry, NMR Spectroscopy, Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, The Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: Wienk
authors.affiliation: Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Johanne H
authors.initials: JH
authors.lastname: Ellenbroek
authors.affiliation: Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands; Hubrecht Institute/KNAW and University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Eelco J P
authors.initials: EJ
authors.lastname: de Koning
authors.affiliation: Molecular Cancer Research and Cancer Genomics Netherlands, Center for Molecular Medicine, UMC Utrecht, Utrecht, The Netherlands.
authors.forename: Johannes L
authors.initials: JL
authors.lastname: Bos
authors.affiliation: Department of Biochemistry, University of Kassel, Kassel, Germany.
authors.forename: Friedrich W
authors.initials: FW
authors.lastname: Herberg
authors.affiliation: BIOLOG Life Science Institute, Bremen, Germany.
authors.forename: Hans-Gottfried
authors.initials: HG
authors.lastname: Genieser
authors.affiliation: Galapagos BV, CR Leiden, The Netherlands.
authors.forename: Richard A J
authors.initials: RA
authors.lastname: Janssen
authors.affiliation: Molecular Cancer Research and Cancer Genomics Netherlands, Center for Molecular Medicine, UMC Utrecht, Utrecht, The Netherlands.
authors.forename: Holger
authors.initials: H
authors.lastname: Rehmann
mesh_terms: D001665:Binding Sites; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D000242:Cyclic AMP / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D020662:Guanine Nucleotide Exchange Factors / Q000819:agonists* / Q000737:chemistry / Q000502:physiology; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D011485:Protein Binding
chemical_list: D020662:Guanine Nucleotide Exchange Factors; D007328:Insulin; C116122:RAPGEF3 protein, human; C442864:RAPGEF4 protein, human; D000242:Cyclic AMP