PMX-53

PMX-53 (3D53) is a synthetic peptidic and a potent and orally active complement C5a receptor (CD88) antagonist with an IC₅₀ of 20 nM. PMX-53 is also a low-affinity MrgX2 agonist that stimulates MrgX2-mediated mast cell degranulation. PMX-53 specifically binds to C5aR1 and does not bind to the second C5aR (C5L2) and C3aR. PMX-53 has anti-inflammatory, anticancer and antiatherosclerotic effects^{[1][2][3][4][5][6]}. IC50 & Target:IC50: 20 nM (Complement C5a receptor)^[4]
MrgX2^[1] In Vitro: PMX-53 is a potent CD88 antagonist and inhibits C5a-induced neutrophil myeloperoxidase release and chemotaxis with IC₅₀ values of 22 nM and 75 nM, respectively^[1].
PMX-53 (10 nM) inhibits C5a-induced Ca²⁺ mobilization in HMC-1 cells, but at higher concentrations( ≥30 nM) it causes degranulation in LAD2 mast cells, CD34⁺ cell-derived mast cells, and RBL-2H3 cells stably expressing MrgX2. Replacement of Trp with Ala and Arg with dArg abolishes the ability of PMX-53 to inhibit C5a-induced Ca²⁺ mobilization in HMC-1 cells and to cause degranulation in RBL-2H3 cells expressing MrgX2^[1]. In Vivo: PMX-53 (0.3-3 mg/kg; subcutaneous injection; once; male Wistar rats) treatment inhibits the hypernociception induced by zymosan-activated serum and C5a but not by the direct-acting hypernociceptive mediators, prostaglandin E2 and dopamine^[2].
Local pretreatment of rats with PMX-53 (60-180 μg per paw) inhibits zymosan-, carrageenan-, lipopolysaccharide (LPS)- and antigen-induced hypernociception^[2].
Pharmacokinetic analyses have shown that PMX-53 (3D53) appears in the plasma within 5 min of oral administration (3 mg/kg) to rats, with peak blood levels of approximately 0.3 μM being reached within 20 min The plasma elimination half-life was approximately 70 min in this case^[3].
The non-acetylated version of PMX-53 (3D53) binds to isolated mouse neutrophils with a K_d value of 30 nM (mouse C5a binds with a K_d value of 0.3 nM) and inhibits mouse C5a-induced chemotaxis with an IC₅₀ value of 0.5 nM^[3].