Complement inhibitor

Zahedi R. Wisnieski J, Davis AE 3rd Role of the P2 residue of complement-1 inhibitor (Ala443) in determination of target protease specificity inhibi- 93 tion of complement and contact system proteases. J Immunol 1997 159 983-988. 

Complement 1 Inhibitor. Cl-Inh is reduced in sepsis. Substitution with Cl-Inh concentration has been safely performed and preliminary results are consistent with a beneficial effect on hypotension in patients with septic shock. Whether this therapy may reduce mortality has still to be established (H6). 

Weng, W.K. and Levy, R., Expression of complement Inhibitors CD46, CD55, and CD59 on tumor cells does not predict clinical outcome after rituximab treatment in follicular non-Hodgkin lymphoma. Blood, 98, 1352-1357, 2001. 

Soliris is for the treatment of paroxysmal nocturnal hemoglobinuria (PNH). PNH is a chronic disease where a patient s oxygen-carrying red blood cells are missing the normally present complement inhibitors. The cells are therefore abnormally fragile and inadvertently destroyed by normal complement activation. 

PNH is caused by a mutation in certain types of adult blood cells. Because of this mutation, certain types of proteins, including complement inhibitors, are unable to attach to the surface of the cell, as is normally the case. More specifically, the PNH mutation prevents the assembly of a fatty tail, known as a glycosyl-phosphatidylinositol (GPI) anchor, a necessary step in surface attachment of some proteins. 

CHO COOH. Oxidation of the complement inhibitor K-76 (1) in 1 N NaOH with excess Ag20 cleanly affords a monocarboxylic acid, shown to be 2 by lactonization experiments. Thus the formyl group meta to the phenolic hydroxyl is the... 

Cardiovascular In rodents, lymphohistiocytic infiltrates have been observed in the heart and in the perivascular space in various organs. Tissue macrophages in the heart can contain basophilic granules. In monkeys, no changes in ECG, heart rate, or blood pressure have been observed with numerous oligonucleotides. Under conditions when complement is activated, changes in blood pressure and cardiovascular collapse due to hypotension have been observed [55], but we have shown this to be related to complement activation rather than a direct effect on the cardiovascular system. (Of course, other mechanisms for hypotension could occur with other chemistries. For example, if an oligonucleotide formulation or its metabolic products chelates calcium, reductions in ionizable calcium could also produce a hypotensive crisis.) For most PS ODNs the most likely cause of hypotension is complement activation as demonstrated with complement inhibitors. 

The Inhibition of Platelet Aggregation by Complement Inhibitors, Thrombos. Diathes. Haemorrh. (1969) 22, 460. 

Surprisingly, additions of electrophiles, radicals, and nucleophiles to methylene cyclopropane have rarely been executed under synthetic conditions. A sequence leading to the complement inhibitor K-76 published recently" very smartly takes advantage of a methylenecyclopropane participation in the polyene cyclization shown in equation 197. Hydroxylation of the vinylcyclopropane double bond and hydrogenolysis of the three membered ring are subsequent essential reactions. 

Hereditary angioedema, with deficiency of Cj-esterase inhibitor (a complement inhibitor), may not respond to antihistamines or corticosteroid but only to fresh frozen plasma or preferably Cj-inhibitor concentrate. Delay in initiating the treatment may lead to death from laryngeal oedema (try adrenaline (epinephrine) i.m. in severe cases). For long-term prophylaxis an androgen (stanozolol, danazol) can be effective. 

Synthesis of monomethyl resistomycine 26, which requires 1-aminophthalan, is shown above. The complement inhibitor K-76,28 has also been synthesised in racemic form, from phthalan 27. The steps involved are as shown below... 

The complement inhibitor K-76 28) contains a 2,3-dihydrobenzofuran moiety. The key step is the formation of 73, which is obtained by an aromatic lithiation reactions. This was then converted to K-76... 

Recent pharmacological therapies that have shown promise in clinical trials include adenosine, pexelizumab, and glucose-insulin-potassium (GIK). In the AMISTAD-2 trial, patients treated with high-dose adenosine had a smaller infarct size (11% vs. 26% p = 0.03) (77). The COMMA trial evaluated the effect of pexelizumab, a novel C5 complement inhibitor, to reduce reperfusion injury (78). Although there was no difference in infarct size between study groups, there was a surprising mortality benefit in patients treated with pexelizumab bolus... 

Wong J, Quinn CM, Brown AJ (2006) SREBP-2 positively regulates transcription of the cholesterol efflux gene, ABCAl, by generating oxysterol hgands for LXR. Biochem J 400 485 91 Woodruff TM, Costini KJ, Taylor SM, Noakes PG (2008) Role of complement in motor neuron disease animal models and therapeutic potential of complement inhibitors. Adv Exp Med Biol 632 143-156... 

Renne R, Zhong W, Herndier B, McGrath M, Abbey N, Ganem D (1996) Lytic growth of Kaposi s sarcoma-associate herpesvirus (human herpesvirus 8) in culture. Nat Med 2 342- 346 Rother RP, Rollins SA, Fodor WL, Albrecht JC, Setter E, Fleckenstein B, Squinto SP (1994) Inhibition of complement-mediated cytolysis by the terminal complement inhibitor of herpesvirus saimiri. J Virol 68 730-737... 

Figure2. Staphylococcal innate immune evasion. The molecules produced by S-aureusthatcounteract the different steps of our innate immune system. SSL-5 (Staphylococcal Superantigen-like 5), Eap (Extracellular adherence protein), CHIPS (Chemotaxis inhibitory protein of Staphylococci), FLIPr (FPRL-1 inhibitory protein), SSL-7 (Staphylococcal Superantigen-like 7), Efb (Extracellular fibrinogen binding protein), Ecb(Extracellularcomplementbindingprotein), protA(protein A), SCI Nl (Staphylococcal Complement inhibitor), SCIN B (Staphylococcal Complementinhibitor-B), SCIN C (Staphylococcal Complement inhibitor-C), SAK (Staphylokinase).

Rooijakkers SH, Ruyken M, Roos A et al. Immune evasion by a staphylococcal complement inhibitor that acts on C3 convertases. Nat Immunol 2005 6 920-927. 

Rooijakkers SH, Milder FJ, Bardocl BV et al. Staphylococcal complement inhibitor structure and active sites. J Immunol 2007 179 2989-2998. 

Finally, S. aureus excretes a number of proteins that specifically block convertase activity. The first described convertase inhibitor is Staphylococcal complement inhibitor (SCIN) (10 kDa), an excreted protein that binds C3 convertases and interferes with all complement pathways. SCIN binding to surface-bound C3 convertases has two major consequences. First, the binding of SCIN to C4b2a and C3bBb impairs the enzymatic activity of the convertases. Second, SCIN stabilizes C3 convertases which impairs the formation of new convertases. These actions result in very potent inhibition of phagocytosis and C5a production. Next to production of SCIN, S. aureus also excretes the proteins SCIN-B and SCIN-C. Both proteins are homolc es of SCIN that share the exact same mechanism of action. ... 

Because the complement system is an evolutionary conserved protein cascade, the observed host specificity of bacterial complement inhibitors is very striking. The Gram-positive proteins SAK, SCIN and ScpB and the Neisserial porin molecules display strict human specificity. In case of Neisserial porin which exclusively binds human C4BP, host-spedfidty of the complement inhibitor bindii may contribute to host specificity of the infection. Understandii the basis for species specificity of complement evasion will hopefully lead to development of better animal models for infectious diseases, for example, creating transgenic mice for human complement inhibitory proteins to study pathc ens such as N. gonorrhoeae. 

Stevenson B, 1-Hage N, Hines MA et al. Dificrential binding of host complement inhibitor factor H by Borrelia burgdorferi rp surface proteins a possible mechanism underlying the expansive host range of Lyme disease spirochetes. Infect Immun 2002 70 491-497. 

Alitalo A, Mcri T, Lanldnen H et al. Complement inhibitor hictor H binding to Lyme disease spirochetes is mediated by inducible expression of multiple plasmid-encoded outer surface protein paralogs. J Immunol 2002 169(7) 3847-3853. 

Jarva H, Ram S, Vogel U et al. Binding of the complement inhibitor C4bp to serogroup B Neisseria meningitidis. J Immunol 2005 174 6299-6307. 

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