Function of PMX-53 as an antagonists

2018-10-09

Introduction 

PMX-53, a chemically synthesized peptide material, is a potent C5a antagonist in human neutrophils and macrophages in vitro, aiming to protect rodents from a number of experimental inflammatory diseases. The anaphylatoxin C5a is generated as a byproduct of complement activation, which interacts with its cognate cell surface G protein-coupled receptor (GPCR; CD88) to activate neutrophils and macrophages.

Pharmacologic action

PMX-53 is a potent C5a antagonist and inhibits C5a-induced neutrophil myeloperoxidase release and chemotaxis with IC50 values of 22 and 75 nM, respectively. As a potent C5a antagonist, PMX-53 (10 nM) inhibited C5a induced Ca2+ mobilization in HMC-1 cells, but at higher concentrations (30 nM) it caused degranulation in LAD2 mast cells, CD34 cell-derived mast cells, and RBL-2H3 cells stably expressing MrgX2. PMX-53 did not, however, activate RBL-2H3 cells expressing MrgX1. Although C5a induced degranulation in LAD2 and CD34 cell-derived mast cells, it did not activate RBL-2H3 cells expressing MrgX1 or MrgX2.

Function

This antagonist has displayed potential therapeutic value in a range of animal models of inflammatory diseases including sepsis, rheumatoid arthritis, inflammatory bowel disease, various ischaemia-reperfusion injuries, and recently in a model of neurodegeneration. Trp and Arg residues are required for the ability of PMX53 to act as both a CD88 antagonist and a MrgX2 agonist.

Pharmacokinetics and metabolism

PMX53 had an oral bioavailability of ~5%. It could potentially reflect absorption through buccal, sublabial or sublingual sites, instead of intestinal/gastric absorption. Alternatively, the relatively prolonged in vivo activity of the drug class due to their non-competitive antagonist pharmacology may also help explain their consistent oral activity in vivo. The drug is an insurmountable antagonist, and is long acting in vivo, behaving as a pseudo-irreversible antagonist. Once daily oral dosing of PMX53 is effective in a variety of rat models of disease despite low circulating. PMX53 is rapidly metabolised in cell free intestinal washings, however, this does not appear to be the limiting factor for oral absorption, since another analogue, PMX205, which is resistant to intestinal metabolism, displays similar oral bioavailability.

References:

Subramanian, H., Kashem, S. W., Collington, S. J., Qu, H., Lambris, J. D., & Ali, H. (2011). PMX-53 as a dual CD88 antagonist and an agonist for Mas-related gene 2 (MrgX2) in human mast cells. Molecular pharmacology, mol-111.

Morgan, M., Bulmer, A. C., Woodruff, T. M., Proctor, L. M., Williams, H. M., Stocks, S. Z., ... & Shiels, I. A. (2008). Pharmacokinetics of a C5a receptor antagonist in the rat after different sites of enteral administration. european journal of pharmaceutical sciences, 33(4-5), 390-398.

Kumar, V., Lee, J. D., Clark, R. J., & Woodruff, T. M. (2018). Development and validation of a LC-MS/MS assay for pharmacokinetic studies of complement C5a receptor antagonists PMX53 and PMX205 in mice. Scientific reports, 8(1), 8101.

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