Design and Evaluation of Heterobivalent PAR1–PAR2 Ligands as Antagonists of Calcium Mobilization

Majewski, Mark W.; Gandhi, Disha M.; Rosas, Ricardo; Kodali, Revathi; Arnold, Leggy A.; Dockendorff, Chris

doi:10.1021/acsmedchemlett.8b00538

Cited by 12 publications

(5 citation statements)

References 39 publications

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“…It is possible that the movement of the tethered ligand into the binding site induces further conformational changes in the receptor, which might have a profound effect on the outside of the helical bundle where the high-affinity binding site of AZ3451 is located, explaining why AZ3451 induces partial inhibition of only the tethered ligand-activated state. A recent paper reported a similar finding, a PAR2 antagonist attached to a PEG linker partially inhibited SLIGKV-induced activation of Ca 2+ signalling via PAR2, with IC 50 = 0.1 µM, however, had no effect on trypsin-induced activation of PAR2 39 . Antagonists that can distinguish between peptide and protease-induced activation of PAR2 provide opportunities to improve our understanding of the endogenous mechanism of activation by proteases.…”

Section: Discussionsupporting

confidence: 59%

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

et al. 2020

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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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Section: Discussionsupporting

confidence: 59%

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

et al. 2020

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“…In the absence of PAR2 activation by the agonist, AZ3451 had no effect on the basal activity of the receptor, which allows it to be considered as a NAM [266]. A similar pattern of activity is demonstrated by heterobivalent PAR1/PAR2 ligands, which are constructed based on PAR1-(RWJ-58259) and PAR2-antagonists (imidazopyridazine derivatives) crosslinked with polyethylene glycol [267]. Such constructs should affect the conformation of the PAR1 and PAR2 allosteric sites, which leads to the inhibition of Gq/11-mediated calcium mobilization in endothelial and cancer cells induced by PAR1-and PAR2-agonists.…”

Section: Small Allosteric Ligands Of Parsmentioning

confidence: 77%

Allosteric Regulation of G-Protein-Coupled Receptors: From Diversity of Molecular Mechanisms to Multiple Allosteric Sites and Their Ligands

Ao¹

2023

Preprint

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A separate group consists of compounds that are able to simultaneously interact with both orthosteric and allosteric sites, which are classified as bitopic GPCR ligands [74, 76-81]. They have two pharmacophores, one of which binds with high affinity to the orthosteric site, while the other, with lower affinity, binds to the allosteric site. If these sites are spatially separated in the receptor, then the pharmacophores in the bitopic ligand must be connected with a flexible linker, the length of which exactly corresponds to the distance between the orthosteric and allosteric sites. At the same time, it is important that the linker does not significantly affect the conformational rearrangements in the receptor caused by its activation by orthosteric and (or) allosteric agonists [74, 79].

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“…In the absence of PAR2 activation by the agonist, AZ3451 had no effect on the basal activity of the receptor, which allows it to be considered as a NAM [ 269 ]. A similar pattern of activity is demonstrated by heterobivalent PAR1/PAR2 ligands, which are constructed based on PAR1- (RWJ-58259) and PAR2-antagonists (imidazopyridazine derivatives) cross-linked with polyethylene glycol [ 270 ]. Such constructs should affect the conformation of the PAR1 and PAR2 allosteric sites, which leads to the inhibition of G q/11 -mediated calcium mobilization in endothelial and cancer cells induced by PAR1- and PAR2-agonists.…”

Section: Allosteric Regulators Of Proteinase-activated Receptorsmentioning

confidence: 93%

Allosteric Regulation of G-Protein-Coupled Receptors: From Diversity of Molecular Mechanisms to Multiple Allosteric Sites and Their Ligands

2023

IJMS

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Allosteric regulation is critical for the functioning of G protein-coupled receptors (GPCRs) and their signaling pathways. Endogenous allosteric regulators of GPCRs are simple ions, various biomolecules, and protein components of GPCR signaling (G proteins and β-arrestins). The stability and functional activity of GPCR complexes is also due to multicenter allosteric interactions between protomers. The complexity of allosteric effects caused by numerous regulators differing in structure, availability, and mechanisms of action predetermines the multiplicity and different topology of allosteric sites in GPCRs. These sites can be localized in extracellular loops; inside the transmembrane tunnel and in its upper and lower vestibules; in cytoplasmic loops; and on the outer, membrane-contacting surface of the transmembrane domain. They are involved in the regulation of basal and orthosteric agonist-stimulated receptor activity, biased agonism, GPCR-complex formation, and endocytosis. They are targets for a large number of synthetic allosteric regulators and modulators, including those constructed using molecular docking. The review is devoted to the principles and mechanisms of GPCRs allosteric regulation, the multiplicity of allosteric sites and their topology, and the endogenous and synthetic allosteric regulators, including autoantibodies and pepducins. The allosteric regulation of chemokine receptors, proteinase-activated receptors, thyroid-stimulating and luteinizing hormone receptors, and beta-adrenergic receptors are described in more detail.

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Design and Evaluation of Heterobivalent PAR1–PAR2 Ligands as Antagonists of Calcium Mobilization

Cited by 12 publications

References 39 publications

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

Allosteric Regulation of G-Protein-Coupled Receptors: From Diversity of Molecular Mechanisms to Multiple Allosteric Sites and Their Ligands

Allosteric Regulation of G-Protein-Coupled Receptors: From Diversity of Molecular Mechanisms to Multiple Allosteric Sites and Their Ligands

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