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  3. Protease-activated receptor-2 ligands reveal orthosteric and allosteric mechanisms of receptor inhibition

Protease-activated receptor-2 ligands reveal orthosteric and allosteric mechanisms of receptor inhibition

  • Commun Biol. 2020 Dec 17;3(1):782. doi: 10.1038/s42003-020-01504-0.
Amanda J Kennedy 1 2,  Linda Sundström 1,  Stefan Geschwindner 3,  Eunice K Y Poon 4,  Yuhong Jiang 4,  Rongfeng Chen 5,  Rob Cooke 6,  Shawn Johnstone 7,  Andrew Madin 8,  Junxian Lim 4,  Qingqi Liu 5,  Rink-Jan Lohman 4,  Anneli Nordqvist 9,  Maria Fridén-Saxin 10,  Wenzhen Yang 5,  Dean G Brown 11,  David P Fairlie 4,  Niek Dekker 12
Affiliations

Affiliations

  • 1 Mechanistic Biology & Profiling, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden.
  • 2 MSD at the Francis Crick Institute, London, UK.
  • 3 Structure & Biophysics, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden.
  • 4 Centre for Inflammation and Disease Research (CIDR) and ARC Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, 4072, Australia.
  • 5 Pharmaron Beijing Co., Ltd., 6 Taihe Road BDA, 100176, Beijing, People's Republic of China.
  • 6 Sosei Heptares, Steinmetz Building, Granta Park, Great Abington, Cambridge, CB21 6DG, UK.
  • 7 Department of Chemistry, IntelliSyn Pharma, 7171 Frederick-Banting, Montreal, QC, H4S 1Z9, Canada.
  • 8 Hit Discovery, Discovery Sciences, R&D, AstraZeneca, Cambridge, UK.
  • 9 Medicinal Chemistry, Cardiovascular, Renal & Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
  • 10 Alliance & Project Management, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Gothenburg, Sweden.
  • 11 Hit Discovery, Discovery Sciences, R&D, AstraZeneca, Boston, MA, USA.
  • 12 Discovery Biology, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden. niek.dekker@astrazeneca.com.
PMID: 33335291 DOI: 10.1038/s42003-020-01504-0
Abstract

Protease-activated receptor-2 (PAR2) has been implicated in multiple pathophysiologies but drug discovery is challenging due to low small molecule tractability and a complex activation mechanism. Here we report the pharmacological profiling of a potent new agonist, suggested by molecular modelling to bind in the putative orthosteric site, and two novel PAR2 antagonists with distinctly different mechanisms of inhibition. We identify coupling between different PAR2 binding sites. One antagonist is a competitive inhibitor that binds to the orthosteric site, while a second antagonist is a negative allosteric modulator that binds at a remote site. The allosteric modulator shows probe dependence, more effectively inhibiting peptide than protease activation of PAR2 signalling. Importantly, both antagonists are active in vivo, inhibiting PAR2 agonist-induced acute paw inflammation in rats and preventing activation of mast cells and neutrophils. These results highlight two distinct mechanisms of inhibition that potentially could be targeted for future development of drugs that modulate PAR2.

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