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Selective Photoaffinity Probe That Enables Assessment of Cannabinoid CB2 Receptor Expression and Ligand Engagement in Human Cells.

  • Soethoudt M Laboratorium für Organische Chemie , Eidgenössische Technische Hochschule Zürich , Vladimir-Prelog-Weg 3 , Zürich 8093 , Switzerland.
  • Stolze SC Department of Rheumatology , Leiden University Medical Center , Albinusdreef 2 , Leiden 2333 ZA , The Netherlands.
  • Westphal MV Roche Innovation Center Basel , F. Hoffmann-La Roche Ltd. , Grenzacherstrasse 124 , Basel 4070 , Switzerland.
  • van Stralen L Laboratory of Cardiovascular Physiology and Tissue Injury , National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health , 5625 Fishers Lane , Rockville , Maryland 20852 , United States.
  • Martella A Roche Innovation Center Basel , F. Hoffmann-La Roche Ltd. , Grenzacherstrasse 124 , Basel 4070 , Switzerland.
  • van Rooden EJ Laboratory of Cardiovascular Physiology and Tissue Injury , National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health , 5625 Fishers Lane , Rockville , Maryland 20852 , United States.
  • Guba W Laboratorium für Organische Chemie , Eidgenössische Technische Hochschule Zürich , Vladimir-Prelog-Weg 3 , Zürich 8093 , Switzerland.
  • Varga ZV Department of Rheumatology , Leiden University Medical Center , Albinusdreef 2 , Leiden 2333 ZA , The Netherlands.
  • Deng H
  • van Kasteren SI
  • Grether U
  • IJzerman AP
  • Pacher P
  • Carreira EM
  • Overkleeft HS
  • Ioan-Facsinay A
  • Heitman LH
  • van der Stelt M
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  • 2018-02-09
Published in:
  • Journal of the American Chemical Society. - 2018
Alkynes
HL-60 Cells
Humans
Ligands
Molecular Structure
Morpholines
Photoaffinity Labels
Pyridines
Receptor, Cannabinoid, CB2
English Chemical tools and methods that report on G protein-coupled receptor (GPCR) expression levels and receptor occupancy by small molecules are highly desirable. We report the development of LEI121 as a photoreactive probe to study the type 2 cannabinoid receptor (CB2R), a promising GPCR to treat tissue injury and inflammatory diseases. LEI121 is the first CB2R-selective bifunctional probe that covalently captures CB2R upon photoactivation. An incorporated alkyne serves as ligation handle for the introduction of reporter groups. LEI121 enables target engagement studies and visualization of endogenously expressed CB2R in HL-60 as well as primary human immune cells using flow cytometry. Our findings show that strategically functionalized probes allow monitoring of endogenous GPCR expression and engagement in human cells using tandem photoclick chemistry and hold promise as biomarkers in translational drug discovery.
Language
  • English
Open access status
hybrid
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Persistent URL
https://folia.unifr.ch/global/documents/15722
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