Structure-Guided Design of Selective Epac1 and Epac2 Agonists
Publication date
2015-01-01
Authors
Schwede, Frank
Bertinetti, Daniela
Langerijs, Carianne N.
Hadders, Michael A.
Wienk, Hans
Ellenbroek, Johanne H.
de Koning, Eelco J. P.
Bos, Hans
Herberg, Friedrich W.
Genieser, Hans Gottfried
Editors
Advisors
Supervisors
Document Type
Article
Metadata
Show full item recordCollections
License
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.
Keywords
General Agricultural and Biological Sciences, General Biochemistry,Genetics and Molecular Biology, General Immunology and Microbiology, General Neuroscience, Journal Article, Research Support, Non-U.S. Gov't
Citation
Schwede, F, Bertinetti, D, Langerijs, C N, Hadders, M A, Wienk, H, Ellenbroek, J H, de Koning, E J P, Bos, J L, Herberg, F W, Genieser, H G, Janssen, R A J & Rehmann, H 2015, 'Structure-Guided Design of Selective Epac1 and Epac2 Agonists', PLoS Biology, vol. 13, no. 1, 1002038. https://doi.org/10.1371/journal.pbio.1002038