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Murepavadin, a Small Molecule Host Defense Peptide Mimetic, Activates Mast Cells via MRGPRX2 and MrgprB2

Amponnawarat, A;Chompunud Na Ayudhya, C;Ali, H;

Pseudomonas aeruginosa is a frequent cause of hospital-acquired wound infection and is
difficult to treat because it forms biofilms and displays antibiotic resistance. Previous
studies in mice demonstrated that mast cells (MCs) not only contribute to P. aeruginosa
eradication but also promote wound healing via an unknown mechanism. We recently
reported that host defense peptides (HDPs) induce human MC degranulation via

Masrelated G protein-coupled receptor-X2 (MRGPRX2). Small molecule HDP mimetics have
distinct advantages over HDPs because they are inexpensive to synthesize and display
high stability, bioavailability, and low toxicity. Murepavadin is a lipidated HDP mimetic,
(also known as POL7080), which displays antibacterial activity against a broad panel of
multi-drug-resistant P. aeruginosa. We found that murepavadin induces Ca2+
mobilization, degranulation, chemokine IL-8 and CCL3 production in a human MC line
(LAD2 cells) endogenously expressing MRGPRX2. Murepavadin also caused
degranulation in RBL-2H3 cells expressing MRGPRX2 but this response was
significantly reduced in cells expressing missense variants within the receptor’s ligand
binding (G165E) or G protein coupling (V282M) domains. Compound 48/80 induced

barrestin recruitment and promoted receptor internalization, which resulted in substantial
decrease in the subsequent responsiveness to the MRGPRX2 agonist. By contrast,
murepavadin did not cause b-arrestin-mediated MRGPRX2 regulation. Murepavadin
induced degranulation in mouse peritoneal MCs via MrgprB2 (ortholog of human
MRGPRX2) and caused increased vascular permeability in wild-type mice but not in
MrgprB2-/- mice. The data presented herein demonstrate that murepavadin activates
human MCs via MRGPRX2 and murine MCs via MrgprB2 and that MRGPRX2 is resistant
to b-arrestin-mediated receptor regulation. Thus, besides its direct activity against P.
aeruginosa, murepavadin may contribute to bacterial clearance and promote wound
healing by harnessing MC’s immunomodulatory property via the activation of MRGPRX2.