Optical control of a receptor-linked guanylyl cyclase using a photoswitchable peptidic hormone

Tom Podewin, Johannes Broichhagen, Christina Frost, Dieter Groneberg, Julia Ast, Helena Meyer-Berg, Nicholas H.F. Fine, Andreas Friebe, Martin Zacharias, David J. Hodson, Dirk Trauner, Anja Hoffmann-Röder

Research output: Contribution to journalArticle

Abstract

The optical control over biological function with small photoswitchable molecules has gathered significant attention in the last decade. Herein, we describe the design and synthesis of a small library of photoswitchable peptidomimetics based upon human atrial natriuretic peptide (ANP), in which the photochromic amino acid [3-(3-aminomethyl)phenylazo]phenylacetic acid (AMPP) is incorporated into the peptide backbone. The endogeneous hormone ANP signals via the natriuretic peptide receptor A (NPR-A) through raising intracellular cGMP concentrations, and is involved in blood pressure regulation and sodium homeostasis, as well as lipid metabolism and pancreatic function. The cis- and trans-isomers of one of our peptidomimetics, termed TOP271, exhibit a four-fold difference in NPR-A mediated cGMP synthesis in vitro. Despite this seemingly small difference, TOP271 enables large, optically-induced conformational changes ex vivo and transforms the NPR-A into an endogenous photoswitch. Thus, application of TOP271 allows the reversible generation of cGMP using light and remote control can be afforded over vasoactivity in explanted murine aortic rings, as well as pancreatic beta cell function in islets of Langerhans. This study demonstrates the broad applicability of TOP271 to enzyme-dependent signalling processes, extends the toolbox of photoswitchable molecules to all classes of transmembrane receptors and utilizes photopharmacology to deduce receptor activation on a molecular level.

Original languageEnglish (US)
Pages (from-to)4644-4653
Number of pages10
JournalChemical Science
Volume8
Issue number6
DOIs
StatePublished - 2017

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Guanylate Cyclase-Coupled Receptors
Peptidomimetics
Atrial Natriuretic Factor
Hormones
Pressure regulation
Molecules
Blood pressure
Remote control
Isomers
Sodium
Chemical activation
Amino Acids
Peptides
Enzymes
atrial natriuretic factor receptor A

ASJC Scopus subject areas

  • Chemistry(all)

Cite this

Podewin, T., Broichhagen, J., Frost, C., Groneberg, D., Ast, J., Meyer-Berg, H., ... Hoffmann-Röder, A. (2017). Optical control of a receptor-linked guanylyl cyclase using a photoswitchable peptidic hormone. Chemical Science, 8(6), 4644-4653. https://doi.org/10.1039/c6sc05044a

Optical control of a receptor-linked guanylyl cyclase using a photoswitchable peptidic hormone. / Podewin, Tom; Broichhagen, Johannes; Frost, Christina; Groneberg, Dieter; Ast, Julia; Meyer-Berg, Helena; Fine, Nicholas H.F.; Friebe, Andreas; Zacharias, Martin; Hodson, David J.; Trauner, Dirk; Hoffmann-Röder, Anja.

In: Chemical Science, Vol. 8, No. 6, 2017, p. 4644-4653.

Research output: Contribution to journalArticle

Podewin, T, Broichhagen, J, Frost, C, Groneberg, D, Ast, J, Meyer-Berg, H, Fine, NHF, Friebe, A, Zacharias, M, Hodson, DJ, Trauner, D & Hoffmann-Röder, A 2017, 'Optical control of a receptor-linked guanylyl cyclase using a photoswitchable peptidic hormone', Chemical Science, vol. 8, no. 6, pp. 4644-4653. https://doi.org/10.1039/c6sc05044a
Podewin T, Broichhagen J, Frost C, Groneberg D, Ast J, Meyer-Berg H et al. Optical control of a receptor-linked guanylyl cyclase using a photoswitchable peptidic hormone. Chemical Science. 2017;8(6):4644-4653. https://doi.org/10.1039/c6sc05044a
Podewin, Tom ; Broichhagen, Johannes ; Frost, Christina ; Groneberg, Dieter ; Ast, Julia ; Meyer-Berg, Helena ; Fine, Nicholas H.F. ; Friebe, Andreas ; Zacharias, Martin ; Hodson, David J. ; Trauner, Dirk ; Hoffmann-Röder, Anja. / Optical control of a receptor-linked guanylyl cyclase using a photoswitchable peptidic hormone. In: Chemical Science. 2017 ; Vol. 8, No. 6. pp. 4644-4653.
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