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

• DOI: 10.1038/s42003-020-01504-0
• Publication Date: 2020-12-17T11:04:23Z
• Authors: 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
• Keywords: Allosteric modulator; Competitive antagonist

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 potent new agonist, suggested by molecular modelling bind putative orthosteric site, two novel PAR2 antagonists with distinctly different mechanisms inhibition. We identify coupling between binding sites. One antagonist competitive inhibitor that binds while second negative allosteric modulator at remote site. The shows probe dependence, more effectively inhibiting peptide than protease signalling. Importantly, both are active vivo, agonist-induced acute paw inflammation rats preventing mast cells neutrophils. These results highlight distinct inhibition potentially could be targeted for future development drugs modulate PAR2.