Pharmacokinetics of a C5a receptor antagonist in the rat after different sites of enteral administration

Morgan, Michael; Bulmer, Andrew Cameron; Woodruff, Trent M.; Proctor, Lavinia M.; Williams, Hua M.; Stocks, Shelli Z.; Pollitt, Sandra; Taylor, Stephen M.; Shiels, Ian A.

doi:10.1016/j.ejps.2008.01.009

Cited by 20 publications

(19 citation statements)

References 25 publications

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“…It is a cyclic hexapeptide (structure: Ace-Phe-[Orn-Pro-dCha-Trp-Arg]), which has low nanomolar potency, and efficacy in a wide range of species [12], making it an ideal research tool [3]. One potential drawback for the clinical use of this compound, however, is its peptidic nature and low oral bioavailability [13], which has limited its commercial development [9]. …”

Section: Introductionmentioning

confidence: 99%

Insights into the mechanism of C5aR inhibition by PMX53 via implicit solvent molecular dynamics simulations and docking

et al. 2014

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BackgroundThe complement protein C5a acts by primarily binding and activating the G-protein coupled C5a receptor C5aR (CD88), and is implicated in many inflammatory diseases. The cyclic hexapeptide PMX53 (sequence Ace-Phe-[Orn-Pro-dCha-Trp-Arg]) is a full C5aR antagonist of nanomolar potency, and is widely used to study C5aR function in disease.ResultsWe construct for the first time molecular models for the C5aR:PMX53 complex without the a priori use of experimental constraints, via a computational framework of molecular dynamics (MD) simulations, docking, conformational clustering and free energy filtering. The models agree with experimental data, and are used to propose important intermolecular interactions contributing to binding, and to develop a hypothesis for the mechanism of PMX53 antagonism.ConclusionThis work forms the basis for the design of improved C5aR antagonists, as well as for atomic-detail mechanistic studies of complement activation and function. Our computational framework can be widely used to develop GPCR-ligand structural models in membrane environments, peptidomimetics and other chemical compounds with potential clinical use.

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Section: Introductionmentioning

confidence: 99%

Insights into the mechanism of C5aR inhibition by PMX53 via implicit solvent molecular dynamics simulations and docking

et al. 2014

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“…Like many peptides, PMX53 has low oral bioavailability, but its long-lasting effect means that even once-daily oral dosing is sufficient to maintain circulating levels in the rat (Morgan et al, 2008). The development of PMX53 has been discontinued (http://www.evaluatepharma.…”

Section: Structure Of Complement Peptidesmentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. LXXXVII. Complement Peptide C5a, C4a, and C3a Receptors

Klos

Wende²,

Wareham³

et al. 2013

Pharmacol Rev

224

245

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“…The anti-C5 mAb eculizumab was tested in RA but was not progressed; data on the Alexion Web site shows that although the primary end point was missed, a positive response was achieved at 3 mo in patients stratified according to baseline TCC despite the low dose (8 mg/kg) used. Trials of the C5aR antagonist PMX53 also failed, but this agent has failed in all trials likely because of limited bioavailability (42). Our data suggest that effective inhibition of C5a/C5aR would be therapeutic in RA.…”

Section: Discussionmentioning

confidence: 94%

Functional analysis of a complement polymorphism (rs17611) associated with Rheumatoid Arthritis

Giles¹,

Morgan²,

Harris³

2013

Molecular Immunology

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Complement is implicated in the pathogenesis of rheumatoid arthritis (RA); elevated levels of complement activation products have been measured in plasma, synovial fluid, and synovial tissues of patients. Complement polymorphisms are associated with RA in genome-wide association studies. Coding-region polymorphisms may directly impact protein activity; indeed, we have shown that complement polymorphisms affecting a single amino acid change cause subtle changes in individual component function that in combination have dramatic effects on complement activity and disease risk. In this study, we explore the functional consequences of a single nucleotide polymorphism (SNP) (rs17611) encoding a V802I polymorphism in C5 and propose a mechanism for its link to RA pathology. Plasma levels of C5, C5a, and terminal complement complex were measured in healthy and RA donors and correlated to rs17611 polymorphic status. Impact of the SNP on C5 functionality was assessed. Plasma C5a levels were significantly increased and C5 levels significantly lower with higher copy number of the RA risk allele for rs17611, suggesting increased turnover of C5 V802. Functional assays using purified C5 variants revealed no significant differences in lytic activity, suggesting that increased C5 V802 turnover was not mediated by complement convertase enzymes. C5 is also cleaved in vivo by proteases; the C5 V802 variant was more sensitive to cleavage with elastase and the "C5a" generated was biologically active. We hypothesize that this SNP in C5 alters the rate at which elastase generates active C5a in rheumatoid joints, hence recruiting neutrophils to the site thus maintaining a state of inflammation in arthritic joints.

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Pharmacokinetics of a C5a receptor antagonist in the rat after different sites of enteral administration

Cited by 20 publications

References 25 publications

Insights into the mechanism of C5aR inhibition by PMX53 via implicit solvent molecular dynamics simulations and docking

Insights into the mechanism of C5aR inhibition by PMX53 via implicit solvent molecular dynamics simulations and docking

International Union of Basic and Clinical Pharmacology. LXXXVII. Complement Peptide C5a, C4a, and C3a Receptors

Functional analysis of a complement polymorphism (rs17611) associated with Rheumatoid Arthritis

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