Toward drugs for protease-activated receptor 2 (PAR2)

PAR2 has a distinctive functional phenotype among an unusual group of GPCRs called protease activated receptors, which self-activate after cleavage of their N-termini by mainly serine proteases. PAR2 is the most highly expressed PAR on certain immune cells, and it is activated by multiple proteases (but not thrombin) in inflammation. PAR2 is expressed on many types of primary human cells and cancer cells. PAR2 knockout mice and PAR2 agonists and antagonists have implicated PAR2 as a promising target in inflammatory conditions; respiratory, gastrointestinal, metabolic, cardiovascular, and neurological dysfunction; and cancers. This article summarizes salient features of PAR2 structure, activation, and function; opportunities for disease intervention via PAR2; pharmacological properties of published or patented PAR2 modulators (small molecule agonists and antagonists, pepducins, antibodies); and some personal perspectives on limitations of assessing their properties and on promising new directions for PAR2 modulation.