New PAR2 antagonist shows promise against asthma

One of the research foci in the Boitano laboratory is the development of antagonists to the G-protein coupled protease-activated receptor-2 (PAR2) for the long-term purpose of developing drugs to treat asthma and pain. Ms. Hillary V. Schiff, B.S. in Biochemistry and B.A. in French, University of Arizona 2023, took the lead in a recent project, summarized in a 2023 manuscript published in the British Journal of Pharmacology. Ms. Schiff screened peptidomimetic compounds developed in Dr. Josef Vagner’s laboratory that were designed to bind PAR2 for their ability to antagonize the receptor against activating peptidomimetics and two proteases known to activate PAR2 (trypsin and human elastase). She characterized a particular compound, C781, for its ability to antagonize the two distinct signaling pathways downstream of PAR2 activation, b-arrestin/mitogen activated protein kinase (MAPK) signaling and G-protein/Ca²⁺ signaling. Ms. Schiff was able to show that C781 was the first (and so far, only) b-arrestin/MAPK biased PAR2 antagonist -- C781 inhibited protease and PAR2 agonist-induced activation of b-arrestin/MAPK signaling without inhibiting G-protein/Ca²⁺ signaling. Ms. Schiff further expanded this research to an in vivo allergen0-induced asthma model. Working with other members of the laboratory, Ms. Schiff found that C781 was efficacious in eliminating allergen-induced airway hyperresponsiveness, inflammation and to a lesser extent, mucus overproduction, all indicators of allergen0-induced asthma. This was the first indication of a b-arrestin/MAPK biased PAR2 antagonist working in vivo. Importantly, C781 has since been shown by our collaborators to be effective in blocking in vivo inflammatory pain. Ms. Schiff demonstrates the power of undergraduates participating in research at the University of Arizona. She is now at the University of Chicago Pritzker School of Medicine pursuing an M.D. as part of the class of 2027.