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Issue 6, 2017
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Optical control of a receptor-linked guanylyl cyclase using a photoswitchable peptidic hormone

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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.

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

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Supplementary files

Article information


Submitted
15 Nov 2016
Accepted
09 Apr 2017
First published
19 Apr 2017

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2017,8, 4644-4653
Article type
Edge Article

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

T. Podewin, J. Broichhagen, C. Frost, D. Groneberg, J. Ast, H. Meyer-Berg, N. H. F. Fine, A. Friebe, M. Zacharias, D. J. Hodson, D. Trauner and A. Hoffmann-Röder, Chem. Sci., 2017, 8, 4644
DOI: 10.1039/C6SC05044A

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