PMX 205

PMX205 is a cyclic hexapeptide (c[Arg-Trp-D-Cha-Pro-Orn]-Hca), which is an antagonist of the C5a complement receptor. [1]

Human C5a, a complement-derived anaphylatoxin, is a potent mediator of human leukocyte chemotaxis. C5a in particular is a potent inflammatory mediator and signalling through CD88 mediates chemotaxis of leukocytes, vascular permeability could be increased, mast cells release inflammatory mediator and smooth muscle cell contracts and other activities, but all the activities contribute to inflammation and potent tissue damage. C5a-mediated leukocyte chemotaxis release from cytochalasin B-treated cells closely paralleled uptake of the ligand, clearly indicating that it is a receptor-C5a interaction that leads to stimulation of these cellular responses. [2]

PMX205 have been shown to be effective in causing a significant reduction in fibrillar amyloid deposits and activated glia in two mouse models of Alzheimer’s disease. PMX205 -treated rats exhibited reduced striatal lesion size, apoptosis, neutrophil infiltration, and hemorrhage.[3]

PMX205 is used as anti-inflammatory drug. PMX205 significantly prevented DSS-induced colon inflammation, and dealed with PMX205, subjected rats had lower pro-inflammatory. Additionally, the levels of anti-inflammatory cytokines IL-4 and IL-10 were increased. PMX205 did not affect C5a’s levels. The positive effect of PMX205 was seen in two strains of mice of differing sensitivities to DSS inflammation. Pharmacological inhibition of C5a activity by PMX205 is efficacious in preventing DSS-induced colitis.[3]

References:
[1] Delisle Milton RC, Milton SC, Chamberlin AR.  Improving the Fmoc Solid Phase Synthesis of the Cyclic Hexapeptide Complement C5a Antagonist, PMX205. Int J Pept Res Ther. 2011 Dec;17(4):337-342.
[2] Chenoweth DE, Hugli TE.  Demonstration of specific C5a receptor on intact human polymorphonuclear leukocytes. Proc Natl Acad Sci U S A. 1978 Aug;75(8):3943-7.
[3] Jain U, Woodruff TM, Stadnyk AW.  The C5a receptor antagonist PMX205 ameliorates experimentally induced colitis associated with increased IL-4 and IL-10. Br J Pharmacol. 2013 Jan;168(2):488-501.

The C5a receptor antagonist PMX205 ameliorates experimentally induced colitis associated with increased IL-4 and IL-10.[Pubmed:22924972]

Br J Pharmacol. 2013 Jan;168(2):488-501.

BACKGROUND AND PURPOSE: Anti-complement therapies have not been advanced for treating the inflammatory bowel diseases (IBDs) despite a growing body of evidence that blocking C5a protects against induced colitis in rodents. The purpose of this study was to further build on this evidence by examining the efficacy, mechanism and specificity of a potent, non-competitive and orally active C5a receptor (CD88) antagonist, PMX205, in the dextran sulphate sodium (DSS) model of murine innate colitis. EXPERIMENTAL APPROACH: Mice with DSS added to their drinking water were orally administered 100 or 200 mug day(-1) PMX205 in prophylactic and therapeutic regimens. Clinical illness, colon histology and local generation of inflammatory mediators were measured to evaluate the impact of PMX205 on disease. KEY RESULTS: PMX205 significantly prevented DSS-induced colon inflammation in both regimens, associated with lower pro-inflammatory cytokine production and nitrotyrosine staining in colon sections. Additionally, the levels of anti-inflammatory cytokines IL-4 and IL-10 were increased. PMX205 had no significant effect on C5a levels. The beneficial effect of PMX205 was seen in two strains of mice of differing sensitivities to DSS inflammation, but was inactive in mice lacking CD88. CONCLUSIONS AND IMPLICATIONS: Pharmacological inhibition of C5a activity by PMX205 is efficacious in preventing DSS-induced colitis, providing further evidence that targeting CD88 in IBD patients could be a valuable therapeutic option.

Treatment with a C5aR antagonist decreases pathology and enhances behavioral performance in murine models of Alzheimer's disease.[Pubmed:19561098]

J Immunol. 2009 Jul 15;183(2):1375-83.

Alzheimer's disease (AD) is an age-related dementia, characterized by amyloid plaques, neurofibrillary tangles, neuroinflammation, and neuronal loss in the brain. Components of the complement system, known to produce a local inflammatory reaction, are associated with the plaques and tangles in AD brain, and thus a role for complement-mediated inflammation in the acceleration or progression of disease has been proposed. A complement activation product, C5a, is known to recruit and activate microglia and astrocytes in vitro by activation of a G protein-coupled cell-surface C5aR. Here, oral delivery of a cyclic hexapeptide C5a receptor antagonist (PMX205) for 2-3 mo resulted in substantial reduction of pathological markers such as fibrillar amyloid deposits (49-62%) and activated glia (42-68%) in two mouse models of AD. The reduction in pathology was correlated with improvements in a passive avoidance behavioral task in Tg2576 mice. In 3xTg mice, PMX205 also significantly reduced hyperphosphorylated tau (69%). These data provide the first evidence that inhibition of a proinflammatory receptor-mediated function of the complement cascade (i.e., C5aR) can interfere with neuroinflammation and neurodegeneration in AD rodent models, suggesting a novel therapeutic target for reducing pathology and improving cognitive function in human AD patients.

Potent cyclic antagonists of the complement C5a receptor on human polymorphonuclear leukocytes. Relationships between structures and activity.[Pubmed:15044616]

Mol Pharmacol. 2004 Apr;65(4):868-79.

Human C5a is a plasma protein with potent chemoattractant and pro-inflammatory properties, and its overexpression correlates with severity of inflammatory diseases. C5a binds to its G protein-coupled receptor (C5aR) on polymorphonuclear leukocytes (PMNLs) through a high-affinity helical bundle and a low-affinity C terminus, the latter being solely responsible for receptor activation. Potent and selective C5a antagonists are predicted to be effective anti-inflammatory drugs, but no pharmacophore for small molecule antagonists has yet been developed, and it would significantly aid drug design. We have hypothesized that a turn conformation is important for activity of the C terminus of C5a and herein report small cyclic peptides that are stable turn mimics with potent antagonism at C5aR on human PMNLs. A comparison of solution structures for the C terminus of C5a, small acyclic peptide ligands, and cyclic antagonists supports the importance of a turn for receptor binding. Competition between a cyclic antagonist and either C5a or an acyclic agonist for C5aR on PMNLs supports a common or overlapping binding site on the C5aR. Structure-activity relationships for 60 cyclic analogs were evaluated by competitive radioligand binding with C5a (affinity) and myeloperoxidase release (antagonist potency) from human PMNLs, with 20 compounds having high antagonist potencies (IC(50), 20 nM-1 microM). Computer modeling comparisons reveal that potent antagonists share a common cyclic backbone shape, with affinity-determining side chains of defined volume projecting from the cyclic scaffold. These results define a new pharmacophore for C5a antagonist development and advance our understanding of ligand recognition and receptor activation of this G protein-coupled receptor.