Complement: A Host Defense Mechanism Ready for Pharmacological Manipulation?

Johnson, Brian J.

doi:10.1002/jps.2600661005

Cited by 19 publications

(3 citation statements)

References 154 publications

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“…These proteins inhibit the C3 and C5 convertases (multisubunit proteases) by promoting dissociation of the multisubunit complexes and/or by inactivating the complexes through proteolysis (catalyzed by factor I). Several pharmacological agents that regulate or modulate complement activity have been identified by in vitro assay, but most have been shown to be of low activity or toxic (Johnson, 1977;Reynard, 1980;Kalli et al, 1994;Morgan, 1994).…”

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confidence: 99%

Solution structure of Compstatin, a potent complement inhibitor

et al. 1998

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The third component of complement, C3, plays a central role in activation of the classical, alternative, and lectin pathways of complement activation. Recently, we have identified a 13-residue cyclic peptide (named Compstatin) that specifically binds to C3 and inhibits complement activation. To investigate the topology and the contribution of each critical residue to the binding of Compstatin to C3, we have now determined the solution structure using 2D NMR techniques; we have also synthesized substitution analogues and used these to study the structure-function relationships involved. Finally, we have generated an ensemble of a family of solution structures of the peptide with a hybrid distance geometry-restrained simulated-annealing methodology, using distance, dihedral angle, and 3JNH.H,-~o~pling constant restraints. The Compstatin structure contained a type I p-turn comprising the segment GlnS-Asp6-Trp7-Glys. Preference for packing of the hydrophobic side chains of Val3, Val4, and Trp' was observed. The generated structure was also analyzed for consistency using NMR parameters such as NOE connectivity patterns, 3JNH.H,-~o~pling constants, and chemical shifts. Analysis of Ala substitution analogues suggested that Val3, G l d , Asp6, Trp7, and Glys contribute significantly to the inhibitory activity of the peptide. Substitution of Gly' caused a 100-fold decrease in inhibitory potency. In contrast, substitution of Val4, His', His", and Arg" resulted in minimal change in the activity. These findings indicate that specific side-chain interactions and the &turn are critical for preservation of the conformational stability of Compstatin and they might be significant for maintaining the functional activity of Compstatin.The complement system is the first line of immunological defense against foreign pathogens (Muller-Eberhard, 1992). Its activation through the classical, alternative, or lectin pathways leads to the generation of anaphylatoxic peptides C3a and C5a and formation of the C5b-9 membrane attack complex. Complement component C3 plays a central role in activation of all three pathways. Activation of C3 by complement pathway C3 convertases and its subsequent attachment to target surface leads to assembly of the membrane attack complex and ultimately to damage or lysis of the target cells (Frank & Fries, 1991). C3 is unique in that it possesses Reprint requests to:

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confidence: 99%

Solution structure of Compstatin, a potent complement inhibitor

et al. 1998

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“…Anaphylatoxins C3a and C5a are known to increase vascular permeability [15]. As to inhibition of hemorrhage, CVF was one of three different pharmacologic agents capable of inhibiting hemorrhage that had no effects upon neutrophil infiltration.…”

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confidence: 99%

Differential effects of pharmacologic agents on the reverse passive Arthus reaction in guinea pigs

et al. 1984

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Five different pharmacologic agents were examined for their effects upon edema, hemorrhage, and vascular infiltration by neutrophils in the reverse passive Arthus reaction (RPAR) in guinea pigs. Two agents, colchicine (3.0 mg/kg p.o.) and ibuprofen (100 mg/kg p.o.) significantly inhibited all three parameters of RPAR. Cobra venom factor (100 units/kg i.p.) inhibited edema and hemorrhage but it did not inhibit neutrophil infiltration. Aminophylline and sulfinpyrazone (100 mg/kg p.o.) inhibited only hemorrhage; they did not inhibit edema or neutrophil infiltration. The results from these studies with five chemically or biologically unrelated pharmacologic agents suggest that the RPAR in guinea pigs can be separated into its basic components (edema, hemorrhage, and neutrophilic infiltration) by selective inhibitors. Inhibition of edema and hemorrhage, or hemorrhage alone of the two-hour RPAR in guinea pigs is not dependent upon inhibition of neutrophilic infiltration.

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“…According to Johnson, anti complement agents should be useful not only for treating transplantation rejection, but also for alleviating autoimmune disease or immune complex (IC) disease caused by the activation of complement system (2). In spite of the above proposal, there have been no experimental or clinical studies in which an attempted application of anti-complement drug for the treatment of the above diseases was successful.…”

Section: Abstract-effectmentioning

confidence: 99%

Immunopharmacological studies of the aqueous extract of Cinnamomum Cassia (CCAq). II. Effect of CCAq on experimental glomerulonephritis.

Nagai

Saito²,

Takizawa

et al. 1982

Jpn.J.Pharmacol

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Abstract-Effectof the aqueous extract of Cinnamomum Cassia (CCAq) on experimental glomerulonephritis was studied and compared with that of cobra venom factor (CoVF). In rat nephrotoxic serum (NTS) nephritis, CCAq clearly inhibited the excretion of protein into the urine and the increase of peripheral leucocyte counts. The histological score in CCAq administered animals was significantly lower than that in control animals. However, CCAq did not inhibit or lower the serum complement level. Contrary to CCAq, hypocomplementation was observed by the administration of CoVF, and the excretion of protein into urine was inhibited in a high dose group. In immune complex (IC) and autologous IC nephritis in rats, CCAq clearly inhibited the excretion of protein into urine and the elevation of blood urea nitrogen (BUN). The administration of CoVF caused hypocomplementation, but little inhibition of the excretion of urinary protein was observed in both types of immune complex nephritis. The histological score was slightly inhibited by a low dose of CCAq and a high dose of CoVF. In the experi ment employing NZB/NZW F, mice, the proteinurea, the elevation of BUN level, and the production of antibodies were clearly inhibited by the adminis tration of CCAq. Similar inhibition was observed by CoVF at a high dose.

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Complement: A Host Defense Mechanism Ready for Pharmacological Manipulation?

Cited by 19 publications

References 154 publications

Solution structure of Compstatin, a potent complement inhibitor

Solution structure of Compstatin, a potent complement inhibitor

Differential effects of pharmacologic agents on the reverse passive Arthus reaction in guinea pigs

Immunopharmacological studies of the aqueous extract of Cinnamomum Cassia (CCAq). II. Effect of CCAq on experimental glomerulonephritis.

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