Optical control of the β2-adrenergic receptor with opto-prop-2: A cis-active azobenzene analog of propranolol

Reggie Bosma; Nicola C. Dijon; Yang Zheng; Hannes Schihada; Niels J. Hauwert; Shuang Shi; Marta Arimont; Rick Riemens; Hans Custers; Andrea van de Stolpe; Henry F. Vischer; Maikel Wijtmans; Nicholas D. Holliday; Diederik W.D. Kuster; Rob Leurs

doi:10.1016/j.isci.2022.104882

Optical control of the β₂-adrenergic receptor with opto-prop-2: A cis-active azobenzene analog of propranolol

Reggie Bosma
, Nicola C. Dijon
, Yang Zheng
, Hannes Schihada
, Niels J. Hauwert
, Shuang Shi
, Marta Arimont
, Rick Riemens
, Hans Custers
, Andrea van de Stolpe
, Henry F. Vischer
, Maikel Wijtmans
, Nicholas D. Holliday
, Diederik W.D. Kuster
, Rob Leurs^*

^*Corresponding author for this work

AIMMS

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

In this study, we synthesized and evaluated new photoswitchable ligands for the beta-adrenergic receptors β₁-AR and β₂-AR, applying an azologization strategy to the first-generation beta-blocker propranolol. The resulting compounds (Opto-prop-1, -2, -3) have good photochemical properties with high levels of light-induced trans-cis isomerization (>94%) and good thermal stability (t_1/2 > 10 days) of the resulting cis-isomer in an aqueous buffer. Upon illumination with 360-nm light to PSS_cis, large differences in binding affinities were observed for photoswitchable compounds at β₁-AR as well as β₂-AR. Notably, Opto-prop-2 (VUF17062) showed one of the largest optical shifts in binding affinities at the β₂-AR (587-fold, cis-active), as recorded so far for photoswitches of G protein-coupled receptors. We finally show the broad utility of Opto-prop-2 as a light-dependent competitive antagonist of the β₂-AR as shown with a conformational β₂-AR sensor, by the recruitment of downstream effector proteins and functional modulation of isolated adult rat cardiomyocytes.

Original language	English
Article number	104882
Pages (from-to)	1-19
Number of pages	19
Journal	iScience
Volume	25
Issue number	9
Early online date	5 Aug 2022
DOIs	https://doi.org/10.1016/j.isci.2022.104882
Publication status	Published - 16 Sept 2022

Bibliographical note

Publisher Copyright:
© 2022 The Author(s)

Funding

This work was supported by: NWO XS (OCENW.XS4.267); PPP Allowance (PURSUANCE) made available by Health\u223CHolland, Top Sector Life Sciences & Health (DWDK); German Research Foundation (DFG) (427840891); DTP postgraduate studentship from the Biotechnology and Biological Sciences Research Council (BBSRC) UK; CSC Chinese scholarship grant (202006310016). Conceptualization: M.A. M.W. N.J.H. R.B. R.L.; methodology by D.W.D.K. H.S. M.W. N.C.D. N.J.H. R.B. Y.Z.; formal analysis: H.S. M.W. N.C.D. R.B.; investigation: A.S. D.W.D.K. H.C. H.S. N.C.D. N.J.H. M.A. R.B. R.R. S.S. Y.Z.; writing of the original draft: M.W. R.B. R.L.; review and editing by D.W.D.K. H.F.V. H.S. M.W. N.D.H. N.J.H. R.B. R.L. Y.Z.; visualization: D.W.D.K. H.S. M.W. N.C.D. R.B.; supervision and project administration: M.W. R.B. R.L.; funding acquisition: R.B. N.D.H. D.W.D.K, H.S. R.L. The authors declare no competing interests. This work was supported by: NWO XS (OCENW.XS4.267); PPP Allowance (PURSUANCE) made available by Health\u223CHolland , Top Sector Life Sciences & Health (DWDK); German Research Foundation ( DFG ) (427840891); DTP postgraduate studentship from the Biotechnology and Biological Sciences Research Council ( BBSRC ) UK; CSC Chinese scholarship grant ( 202006310016 ).

Funders	Funder number
Biotechnology and Biological Sciences Research Council
China Scholarship Council	202006310016
Deutsche Forschungsgemeinschaft	427840891
NWO	OCENW.XS4.267
UK Research and Innovation	104882

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 6 Clean Water and Sanitation

Keywords

Biochemical engineering
Biochemical research method
Photomedicine

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10.1016/j.isci.2022.104882

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Cite this

Bosma, R., Dijon, N. C., Zheng, Y., Schihada, H., Hauwert, N. J., Shi, S., Arimont, M., Riemens, R., Custers, H., van de Stolpe, A., Vischer, H. F., Wijtmans, M., Holliday, N. D., Kuster, D. W. D., & Leurs, R. (2022). Optical control of the β₂-adrenergic receptor with opto-prop-2: A cis-active azobenzene analog of propranolol. iScience, 25(9), 1-19. Article 104882. https://doi.org/10.1016/j.isci.2022.104882

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title = "Optical control of the β2-adrenergic receptor with opto-prop-2: A cis-active azobenzene analog of propranolol",

abstract = "In this study, we synthesized and evaluated new photoswitchable ligands for the beta-adrenergic receptors β1-AR and β2-AR, applying an azologization strategy to the first-generation beta-blocker propranolol. The resulting compounds (Opto-prop-1, -2, -3) have good photochemical properties with high levels of light-induced trans-cis isomerization (>94\%) and good thermal stability (t1/2 > 10 days) of the resulting cis-isomer in an aqueous buffer. Upon illumination with 360-nm light to PSScis, large differences in binding affinities were observed for photoswitchable compounds at β1-AR as well as β2-AR. Notably, Opto-prop-2 (VUF17062) showed one of the largest optical shifts in binding affinities at the β2-AR (587-fold, cis-active), as recorded so far for photoswitches of G protein-coupled receptors. We finally show the broad utility of Opto-prop-2 as a light-dependent competitive antagonist of the β2-AR as shown with a conformational β2-AR sensor, by the recruitment of downstream effector proteins and functional modulation of isolated adult rat cardiomyocytes.",

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Bosma, R, Dijon, NC, Zheng, Y, Schihada, H, Hauwert, NJ, Shi, S, Arimont, M, Riemens, R, Custers, H, van de Stolpe, A, Vischer, HF , Wijtmans, M, Holliday, ND, Kuster, DWD & Leurs, R 2022, 'Optical control of the β₂-adrenergic receptor with opto-prop-2: A cis-active azobenzene analog of propranolol', iScience, vol. 25, no. 9, 104882, pp. 1-19. https://doi.org/10.1016/j.isci.2022.104882

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T1 - Optical control of the β2-adrenergic receptor with opto-prop-2

T2 - A cis-active azobenzene analog of propranolol

AU - Bosma, Reggie

AU - Dijon, Nicola C.

AU - Zheng, Yang

AU - Schihada, Hannes

AU - Hauwert, Niels J.

AU - Shi, Shuang

AU - Arimont, Marta

AU - Riemens, Rick

AU - Custers, Hans

AU - van de Stolpe, Andrea

AU - Vischer, Henry F.

AU - Wijtmans, Maikel

AU - Holliday, Nicholas D.

AU - Kuster, Diederik W.D.

AU - Leurs, Rob

PY - 2022/9/16

Y1 - 2022/9/16

N2 - In this study, we synthesized and evaluated new photoswitchable ligands for the beta-adrenergic receptors β1-AR and β2-AR, applying an azologization strategy to the first-generation beta-blocker propranolol. The resulting compounds (Opto-prop-1, -2, -3) have good photochemical properties with high levels of light-induced trans-cis isomerization (>94%) and good thermal stability (t1/2 > 10 days) of the resulting cis-isomer in an aqueous buffer. Upon illumination with 360-nm light to PSScis, large differences in binding affinities were observed for photoswitchable compounds at β1-AR as well as β2-AR. Notably, Opto-prop-2 (VUF17062) showed one of the largest optical shifts in binding affinities at the β2-AR (587-fold, cis-active), as recorded so far for photoswitches of G protein-coupled receptors. We finally show the broad utility of Opto-prop-2 as a light-dependent competitive antagonist of the β2-AR as shown with a conformational β2-AR sensor, by the recruitment of downstream effector proteins and functional modulation of isolated adult rat cardiomyocytes.

AB - In this study, we synthesized and evaluated new photoswitchable ligands for the beta-adrenergic receptors β1-AR and β2-AR, applying an azologization strategy to the first-generation beta-blocker propranolol. The resulting compounds (Opto-prop-1, -2, -3) have good photochemical properties with high levels of light-induced trans-cis isomerization (>94%) and good thermal stability (t1/2 > 10 days) of the resulting cis-isomer in an aqueous buffer. Upon illumination with 360-nm light to PSScis, large differences in binding affinities were observed for photoswitchable compounds at β1-AR as well as β2-AR. Notably, Opto-prop-2 (VUF17062) showed one of the largest optical shifts in binding affinities at the β2-AR (587-fold, cis-active), as recorded so far for photoswitches of G protein-coupled receptors. We finally show the broad utility of Opto-prop-2 as a light-dependent competitive antagonist of the β2-AR as shown with a conformational β2-AR sensor, by the recruitment of downstream effector proteins and functional modulation of isolated adult rat cardiomyocytes.

KW - Biochemical engineering

KW - Biochemical research method

KW - Photomedicine

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