PMX-53 is an effective c5a receptor antagonist (ic50 = 20 nm), which inhibits C5a-induced hypernociception in rats, inhibits lung metastasis in a mouse breast cancer model and reduces atherosclerotic lesions in a mouse model of atherosclerosis. It also is an agonist for Mas-related gene 2 (MrgX2) in human mast cells.
CAT No: R0880
CAS No:219639-75-5
Synonyms/Alias:PMX-53;219639-75-5;PMX 53;PMX53;CHEMBL41547;(2S)-2-acetamido-N-[(3S,9S,12S,15R,18S)-15-(cyclohexylmethyl)-9-[3-(diaminomethylideneamino)propyl]-12-(1H-indol-3-ylmethyl)-2,8,11,14,17-pentaoxo-1,7,10,13,16-pentazabicyclo[16.3.0]henicosan-3-yl]-3-phenylpropanamide;(S)-N-((3R,6S,9S,15S,20aS)-6-((1H-indol-3-yl)methyl)-3-(cyclohexylmethyl)-9-(3-guanidinopropyl)-1,4,7,10,16-pentaoxoicosahydropyrrolo[1,2-a][1,4,7,10,13]pentaazacyclooctadecin-15-yl)-2-acetamido-3-phenylpropanamide;AcF-[OP(D-Cha)WR];Ac-Phe-[Orn-Pro-cha-Trp-Arg];C5aR-AP;GTPL579;PMX53?;SCHEMBL12971688;SCHEMBL16492460;Ac-(cyclo-2,6)-F-[OPdChaWR];BDBM50111445;s6239;AKOS040749221;CID 6918468;DA-56944;HY-106178;CS-0025111;G13382;Q27088422;Z4761586611;
PMX 53 is a synthetic cyclic peptide known for its potent and selective antagonism of the complement component 5a receptor (C5aR, CD88). As a well-characterized peptide inhibitor, it plays a significant role in modulating innate immune responses by interfering with C5a-mediated signaling pathways. Its unique structural features and receptor specificity have made it a valuable tool for probing the mechanisms of complement activation and inflammatory cascades in various experimental systems. PMX 53's stability and receptor affinity support its widespread adoption in immunological research, allowing for precise interrogation of C5aR-dependent processes in both in vitro and in vivo models.
Immunology research: PMX 53 is extensively used to investigate the role of C5aR signaling in innate immunity and inflammatory response. By selectively blocking C5aR, researchers can elucidate the downstream effects of complement activation, including leukocyte recruitment, cytokine release, and tissue injury mechanisms. This peptide inhibitor enables the dissection of C5a-driven pathways in experimental models, providing critical insight into the molecular underpinnings of inflammation, autoimmunity, and host-pathogen interactions.
Inflammation pathway studies: As a targeted C5aR antagonist, PMX 53 is instrumental in delineating the specific contributions of complement-derived anaphylatoxins to inflammatory disease models. Its application allows scientists to discriminate between C5a-dependent and independent signaling events, thereby clarifying the roles of complement in the progression of diseases such as sepsis, arthritis, and neuroinflammation. The compound's selectivity enhances the reliability of mechanistic studies aiming to characterize the interplay between complement activation and inflammatory mediators.
Peptide functional analysis: The structural attributes and receptor specificity of PMX 53 make it an important reference molecule in peptide-based research. It is frequently employed in comparative studies to evaluate the efficacy and selectivity of novel C5aR antagonists or to benchmark the performance of modified peptide analogs. By serving as a standard in functional assays, it assists in optimizing peptide design strategies and understanding structure-activity relationships within the context of complement inhibition.
Cell signaling investigations: PMX 53 facilitates the study of cell signaling pathways initiated by C5aR activation in various cell types, including neutrophils, macrophages, and endothelial cells. Its use allows for precise modulation of receptor-mediated events, such as intracellular calcium mobilization, chemotaxis, and oxidative burst. Researchers leverage its antagonistic properties to map the downstream signaling networks and to identify key nodes of regulation within immune cell populations, advancing the comprehension of complement-driven cellular responses.
Drug discovery and screening: The selective inhibition profile of PMX 53 makes it a valuable tool in high-throughput screening platforms aimed at identifying new modulators of the complement system. Its well-characterized pharmacological properties provide a reliable benchmark for evaluating the potency and specificity of candidate molecules targeting C5aR. Incorporation of this peptide into assay development enhances the predictive value of preclinical research, supporting the identification and optimization of next-generation complement inhibitors for research use.
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
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