P2pal-18S is a cell-penetrating proteinase-activated receptor-2 (PAR2) antagonist, designed from a structural model of the PAR2 dimer. P2pal-18S is highly selective for PAR2 and has no antagonist activity at the closely related PAR1, PAR4, or CXCR1/2 IL-8 receptors in neutrophil chemotaxis assays. In vitro, P2pal-18S completely suppresses trypsin and mast cell tryptase signaling through PAR2 in neutrophils and colon cancer cells, and in vivo, it is highly efficacious in blocking PAR2-dependent inflammatory responses, preventing the development of neuroinflammatory disease in murine models of multiple sclerosis and experimental autoimmune encephalomyelitis (EAE).
