The most well-studied inhibitors of C5aR1 are Ac-Phe-[Orn-Pro-dCha-Trp-Arg] (3D53 or PMX53) and hydrocinnamate-[Orn-Pro-dCha-Trp-Arg] (PMX205). These small cyclic peptidic molecules specifically target C5aR1 at nanomolar concentrations and act in a pseudo-irreversible and insurmountable manner. PMX205 is a lipophilic analogue of PMX53 that demonstrates improved in vivo stability and efficacy, and has been suggested as a more ideal drug candidate, particularly for neurological diseases. For example, this drug has shown beneficial effects in models of Huntington's disease, amyotrophic lateral sclerosis, spinal cord injury, and in reduction of memory loss in mice with Alzheimer's disease. Both antagonists have been used in numerous experimental inflammatory conditions for over 15 years, and oral and topical PMX53 has also been tested in early Phase I human clinical trials.
Development and validation of a LC-MS/MS assay for pharmacokinetic studies of complement C5a receptor antagonists PMX53 and PMX205 in mice
The purpose of this study was to determine the receptor specificity of C5a-induced mast cell degranulation. To achieve this objective, we used two human mast cell lines, primary CD34 cell-derived mast cells, murine mast cells, and transfected RBL-2H3 cells, as well as C5a and AcPhe(ornithine-Pro-cyclohexylamine-Trp-Arg) (PMX-53), a potent antagonist of CD88. Using these systems, we demonstrate that C5a does not use MrgX1 or MrgX2 for mast cell degranulation, but PMX-53 acts as a dual CD88 antagonist and an MrgX2 agonist. Studies with PMX-53 allowed us to identify specific amino acid residues within PMX-53 that are required for CD88 antagonist and MrgX2 agonist activities.
PMX-53 as a Dual CD88 Antagonist and an Agonist for MasRelated Gene 2 (MrgX2) in Human Mast Cells
