Protease-activated receptors (PARs): mechanisms of action and potential therapeutic modulators in PAR-driven inflammatory diseases

Heuberger, Dorothea M.; Schuepbach, Reto A.

doi:10.1186/s12959-019-0194-8

Table 5 PAR1 signaling modulators

From: Protease-activated receptors (PARs): mechanisms of action and potential therapeutic modulators in PAR-driven inflammatory diseases

Class	Agonist/ Antagonist	Name	Receptor/Cell/Tissue type	Cellular response
Peptide	Agonist	SFLLRN/−NH2	Human	Induces platelet activation [6, 138, 265, 278, 279]
		TFLLRN/−NH2	Human	Induces platelet activation, enhances endothelial barrier permeability [137, 138, 265]
		NPNDKYEPF/−NH2	Human	Induces cytoprotective signaling [28, 187]
		PRSFLLRN/−NH2	Human	Induces platelet activation [86]
		PRSFLLRN/−NH2	Human	Induces ERK1/2 activation [280]
	Antagonist	YFLLRN	Human	Compets with thrombin and PAR1-AP and prevents platelet activation [278, 279]
Peptidomimetic	Antagonist	RWJ-56110	Human	Blunts thrombin and PAR1-AP effects on platelets and vascular endothelial cells [264, 281, 282]
		RWJ-56110	Human	Blocks MMP-1 activaiton in SMCs [87]
		RWJ-58259	Guinea pig	Blocks thrombin and PAR1-AP platelet activation [215, 283]
			Rat	Blocks thrombin induced calcium release in AoSMC Inhibits intimal thickening [111, 215, 264, 273]
			Mouse	Prevents destruction of intestinal barrier [62, 284]
Non-peptide small molecule	Antagonist	FR17113	Human	Blocks PAR1-AP induced platelet activation [285, 286]
		FR17113	Human	Inhibits thrombin and PAR1-AP induced ERK1/2 activation [287]
		ER129614–06	Human	Blocks thrombin and PAR1-AP induced platelet activation [288]
		ER129614–06	Guinea pig	Shows antithrombotic effects [289]
		F16357, F16618	Human	Blocks PAR1-AP induced platelet activation [290]
		F16357, F16618	Rat	Shows antithrombotic effects [291]
		SCH79797	Human	Blocks thrombin and PAR1-AP induced calcium release and platelet activation [292]
		SCH79797	Human, Mouse	Induces NETs formation and increases bacterial killing capacity [293]
		SCH203009	Human	Blocks thrombin and PAR1-AP induced platelet activation [292]
		SCH530348 (vorapaxar)	Human, Monkey	Blocks thrombin and PAR1-AP induced platelet activation [266]
		E5555 (atopaxar)	Human	Blocks thrombin and PAR1-AP induced platelet activation and inhibits thrombus formation [267]
		E5555 (atopaxar)	Guinea pig	Bleeding time not affected [267, 294]
		Q94	Human	Blocks thrombin induced calcium release [295]
		Q94	Mouse	Blocks thrombin induced ERK1/2 activation [296]
Pepducin	Antagonist	P1pal-12	Human	Blocks thrombin induced platelet activation [268]
			Human	Blocks platelet activation [86]
			Human	Blocks MMP-1 induced endothelial damage [297]
			Mouse	Reduces lung vascular damage and sepsis lethality [297, 298]
		P1-pal7 (PZ-128)	Human	Blocks MMP-1 induced Akt signaling in cancer cells [150]
			Human	Blocks platelet activation [86]
			Mouse	Inhibits tumor growth [280]
			Guinea pig	Prevents from systemic platelet activation [86]
Parmodulin	Antagonist	ML161 (Parmodulin-2)	Human	Blocks thrombin and PAR1-AP induced platelet activation [299]
			Human	Blocks thrombin induced inflammatory signaling on endothelial cells [269]
			Mouse	Blocks thrombus formation [300]
Antibiotic	Antagonist	Doxycycline	Human	Inhibits thrombin induced cancer cell migration [301, 302]
Antibiotic	Antagonist	Doxycycline	Human	Blocks MMP-1 cleavage [303]
Antibody	Antagonist	ATAP-2 WEDE	Human	Blocks thrombin cleavage of PAR1 and thrombin induced calcium release [147]

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ISSN: 1477-9560

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