Communications Biology (Dec 2020)
Protease-activated receptor-2 ligands reveal orthosteric and allosteric mechanisms of receptor inhibition
- Amanda J. Kennedy,
- Linda Sundström,
- Stefan Geschwindner,
- Eunice K. Y. Poon,
- Yuhong Jiang,
- Rongfeng Chen,
- Rob Cooke,
- Shawn Johnstone,
- Andrew Madin,
- Junxian Lim,
- Qingqi Liu,
- Rink-Jan Lohman,
- Anneli Nordqvist,
- Maria Fridén-Saxin,
- Wenzhen Yang,
- Dean G. Brown,
- David P. Fairlie,
- Niek Dekker
Affiliations
- Amanda J. Kennedy
- Mechanistic Biology & Profiling, Discovery Sciences, R&D, AstraZeneca
- Linda Sundström
- Mechanistic Biology & Profiling, Discovery Sciences, R&D, AstraZeneca
- Stefan Geschwindner
- Structure & Biophysics, Discovery Sciences, R&D, AstraZeneca
- Eunice K. Y. Poon
- Centre for Inflammation and Disease Research (CIDR) and ARC Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, University of Queensland
- Yuhong Jiang
- Centre for Inflammation and Disease Research (CIDR) and ARC Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, University of Queensland
- Rongfeng Chen
- Pharmaron Beijing Co., Ltd.
- Rob Cooke
- Sosei Heptares, Steinmetz Building
- Shawn Johnstone
- Department of Chemistry, IntelliSyn Pharma
- Andrew Madin
- Hit Discovery, Discovery Sciences, R&D, AstraZeneca
- Junxian Lim
- Centre for Inflammation and Disease Research (CIDR) and ARC Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, University of Queensland
- Qingqi Liu
- Pharmaron Beijing Co., Ltd.
- Rink-Jan Lohman
- Centre for Inflammation and Disease Research (CIDR) and ARC Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, University of Queensland
- Anneli Nordqvist
- Medicinal Chemistry, Cardiovascular, Renal & Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca
- Maria Fridén-Saxin
- Alliance & Project Management, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca
- Wenzhen Yang
- Pharmaron Beijing Co., Ltd.
- Dean G. Brown
- Hit Discovery, Discovery Sciences, R&D, AstraZeneca
- David P. Fairlie
- Centre for Inflammation and Disease Research (CIDR) and ARC Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, University of Queensland
- Niek Dekker
- Discovery Biology, Discovery Sciences, R&D, AstraZeneca
- DOI
- https://doi.org/10.1038/s42003-020-01504-0
- Journal volume & issue
-
Vol. 3,
no. 1
pp. 1 – 13
Abstract
Kennedy et al. report the pharmacological and in vivo profiling of two small molecule PAR2 inhibitors and an agonist. They conclude that while the small molecule agonist and one of the inhibitors bind to the orthosteric PAR2 binding site, the other inhibitor is a negative allosteric modulator, highlighting two distinct mechanisms of inhibition that could be targeted for future development of drugs that modulate PAR2.
