Complement factors and their receptors

Ember, Julia A.; Hugli, Tony E.

doi:10.1016/s0162-3109(97)00088-x

Cited by 149 publications

(118 citation statements)

References 58 publications

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“…The complement component C5a is a 74-amino acid peptide generated during the classical, alternative, and lectin pathways of complement activation (1,2). C5a is a potent chemotactic factor for neutrophils and other leukocytes and is a potent inflammatory mediator.…”

Section: ؉mentioning

confidence: 99%

Identification of a Potent and Orally Active Non-peptide C5a Receptor Antagonist

Sumichika

Sakata

Sato

et al. 2002

Journal of Biological Chemistry

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Section: ؉mentioning

confidence: 99%

Identification of a Potent and Orally Active Non-peptide C5a Receptor Antagonist

Sumichika

Sakata

Sato

et al. 2002

Journal of Biological Chemistry

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“…1a), with less structure in carboxy-terminal residues known to be critical for receptor activation 36 . Mutagenesis of C3a and its receptor support a twosite binding model 37 . The helical bundle residues 1-69 of C3a have high affinity for (but do not activate) the receptor, through multiple positive-charged lysine and arginine residues of C3a making complementary interactions with negative-charged Asp residues in the unusually large extracellular loop 2 (ECL2) at one site of the C3aR 38,39 .…”

mentioning

confidence: 92%

Downsizing a human inflammatory protein to a small molecule with equal potency and functionality

et al. 2013

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A significant challenge in chemistry is to rationally reproduce the functional potency of a protein in a small molecule, which is cheaper to manufacture, non-immunogenic, and also both stable and bioavailable. Synthetic peptides corresponding to small bioactive protein surfaces do not form stable structures in water and do not exhibit the functional potencies of proteins. Here we describe a novel approach to growing small molecules with protein-like potencies from a functionally important amino acid of a protein. A 77-residue human inflammatory protein (complement C3a) important in innate immunity is rationally transformed to equipotent small molecules, using peptide surrogates that incorporate a turninducing heterocycle with correctly positioned hydrogen-bond-accepting atoms. Small molecule agonists (molecular weight o500 Da) examined for receptor affinity and cellular responses have the same high potencies, functional profile and specificity of action as C3a protein, but greater plasma stability and bioavailability.

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“…C5a and C3a are both involved in the mediation of immune responses and inflammatory processes (Ember & Hugli, 1997). While these anaphylatoxins have proinflammatory actions, C3a is responsible for mediating a more specialised set of inflammatory events in vitro.…”

Section: Introductionmentioning

confidence: 99%

Comparative anti‐inflammatory activities of antagonists to C3a and C5a receptors in a rat model of intestinal ischaemia/reperfusion injury

Proctor

Shiels

Reid

et al. 2004

British J Pharmacology

101

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1 Complement activation is implicated in the pathogenesis of intestinal ischaemia-reperfusion injury (I/R), although the relative importance of individual complement components is unclear. A C3a receptor antagonist N(2)-[(2,2-diphenylethoxy)acetyl]-L-arginine (C3aRA) has been compared with a C5a receptor antagonist (C5aRA), AcF-[OPdChaWR], in a rat model of intestinal I/R. 2 C3aRA (IC 50 ¼ 0.15 mM) and C5aRA (IC 50 ¼ 0.32 mM) bound selectively to human polymorphonuclear leukocyte (PMN) C3a and C5a receptors, respectively. Effects on circulating neutrophils and blood pressure in the rat were also assessed. 3 Anaesthetised rats, subjected to intestinal ischaemia (30 min) and reperfusion (120 min), were administered intravenously with either (A) the C3aRA (0.1-1.0 mg kg À1 ); the C5aRA (1.0 mg kg À1 ); the C3aRA þ C5aRA (each 1.0 mg kg À1 ); or vehicle, 45 min prior, or (B) the C3aRA (1.0 mg kg À1 ) or vehicle, 120 min prior to reperfusion. 4 The C3aRA and C5aRA, administered 45 min prior to reperfusion, displayed similar efficacies at ameliorating several disease markers (increased oedema, elevated ALT levels and mucosal damage) of rat intestinal I/R. The combination drug treatment did not result in greater injury reduction than either antagonist alone. However, doses of the C3aRA (0.01-10 mg kg À1 ) caused transient neutropaenia, and the highest dose (10 mg kg À1 ) also caused a rapid and transient hypertension. 5 The C3aRA (1.0 mg kg À1 ), delivered 120 min prior to reperfusion to remove the global effect of C3aRA-induced neutrophil sequestration, did not attenuate the markers of intestinal I/R, despite persistent C3aR antagonism at this time. 6 C3aR antagonism does not appear to be responsible for the anti-inflammatory actions of this C3aRA in intestinal I/R in the rat. Instead, C3aRA-mediated global neutrophil tissue sequestration during ischaemia and early reperfusion may account for the protective effects observed.

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Complement factors and their receptors

Cited by 149 publications

References 58 publications

Identification of a Potent and Orally Active Non-peptide C5a Receptor Antagonist

Identification of a Potent and Orally Active Non-peptide C5a Receptor Antagonist

Downsizing a human inflammatory protein to a small molecule with equal potency and functionality

Comparative anti‐inflammatory activities of antagonists to C3a and C5a receptors in a rat model of intestinal ischaemia/reperfusion injury

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