259
because of the potent toxicity. Other cyclic peptide antagonists include cyclohexylalanine, Trp5, and CD53. Among these, CD53 and its analogs are found to be more
efficient in inhibiting C5a and C5a-mediated neutrophil chemotaxis and cytokine
production from macrophages in vitro (Perricone et al. 2011; Scully et al. 2010).
CD53 stably binds at the transmembrane region of the C5aR near the extracellular
interface through various residues.
Many organic molecules also have been developed as complement inhibitors
such as a fungal metabolite K76 against factor D. Similarly, many nonpeptide
ligands with potential complement protein or its receptor binding ability have been
characterized. WW54011 and NDTP952492 are such ligands which interact at the
similar region where CD53 binds; however, they all fail to form a stable interaction
with the receptor (Mollnes and Kirschfink 2006; Perricone et al. 2011). Many complement inhibitors have proved to be effective in preventing chronic rejections of
xenograft transplant. Antibodies directed against C5 and C8 complement products
are used to prevent hyperacute rejections in transplantation. Several naturally occurring compounds that could potentially block complement components have been
identified. Heparin and its glycosaminoglycan compounds and derivatives are the
epitome of natural complement inhibitors (Mollnes and Kirschfink 2006). Heparin
blocks the interaction between C1q and complement activators and inhibits C3 convertase. Heparin-coated extracorporeal circuits are used to inhibit complement during cardiac surgery (Holers 2016; Kirschfink 2001); however, the success rates are
very low.
A number of promising inhibitors were developed, out of which only one complement inhibitor has been so far approved by FDA for clinical use. Eculizumab is
the first complement-targeting drug approved for treatment (Keating 2013; Rathbone
et al. 2013). It is a monoclonal antibody against C5 protein and is used to treat paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome
(Haspel and Hillmen 2008). This drug has been actually developed for chronic
inflammatory (autoimmune) conditions. Results from ongoing clinical studies are
awaited in patients suffering from autoimmune syndromes. However, some complement inhibitors are either in clinical trial or later steps of preclinical development
(Mollnes and Kirschfink 2006).
10.7.6 Cytokine and Their Receptors as Anti-inflammatory
Targets
Proinflammatory cytokines and their importance in the pathophysiology of many
inflammatory response linked disease conditions were discussed in the previous
section. IL-1 along with IL-6 and TNF-α are some with potential pharmacological
significance. Cytokines prominently activate immune cells and thus amplify
immune response leading to deleterious pathological effects. Proinflammatory cytokines exert their biological response by interacting with respective receptors.
Cytokine–receptor complex would then activate a series of downstream signaling
events involving MAP kinases. MAPKs such as p38, ERK, and SAPK/JNK activate
10 Anti-inflammatory Molecules: Immune System Mediators
because of the potent toxicity. Other cyclic peptide antagonists include cyclohexylalanine, Trp5, and CD53. Among these, CD53 and its analogs are found to be more
efficient in inhibiting C5a and C5a-mediated neutrophil chemotaxis and cytokine
production from macrophages in vitro (Perricone et al. 2011; Scully et al. 2010).
CD53 stably binds at the transmembrane region of the C5aR near the extracellular
interface through various residues.
Many organic molecules also have been developed as complement inhibitors
such as a fungal metabolite K76 against factor D. Similarly, many nonpeptide
ligands with potential complement protein or its receptor binding ability have been
characterized. WW54011 and NDTP952492 are such ligands which interact at the
similar region where CD53 binds; however, they all fail to form a stable interaction
with the receptor (Mollnes and Kirschfink 2006; Perricone et al. 2011). Many complement inhibitors have proved to be effective in preventing chronic rejections of
xenograft transplant. Antibodies directed against C5 and C8 complement products
are used to prevent hyperacute rejections in transplantation. Several naturally occurring compounds that could potentially block complement components have been
identified. Heparin and its glycosaminoglycan compounds and derivatives are the
epitome of natural complement inhibitors (Mollnes and Kirschfink 2006). Heparin
blocks the interaction between C1q and complement activators and inhibits C3 convertase. Heparin-coated extracorporeal circuits are used to inhibit complement during cardiac surgery (Holers 2016; Kirschfink 2001); however, the success rates are
very low.
A number of promising inhibitors were developed, out of which only one complement inhibitor has been so far approved by FDA for clinical use. Eculizumab is
the first complement-targeting drug approved for treatment (Keating 2013; Rathbone
et al. 2013). It is a monoclonal antibody against C5 protein and is used to treat paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome
(Haspel and Hillmen 2008). This drug has been actually developed for chronic
inflammatory (autoimmune) conditions. Results from ongoing clinical studies are
awaited in patients suffering from autoimmune syndromes. However, some complement inhibitors are either in clinical trial or later steps of preclinical development
(Mollnes and Kirschfink 2006).
10.7.6 Cytokine and Their Receptors as Anti-inflammatory
Targets
Proinflammatory cytokines and their importance in the pathophysiology of many
inflammatory response linked disease conditions were discussed in the previous
section. IL-1 along with IL-6 and TNF-α are some with potential pharmacological
significance. Cytokines prominently activate immune cells and thus amplify
immune response leading to deleterious pathological effects. Proinflammatory cytokines exert their biological response by interacting with respective receptors.
Cytokine–receptor complex would then activate a series of downstream signaling
events involving MAP kinases. MAPKs such as p38, ERK, and SAPK/JNK activate
10 Anti-inflammatory Molecules: Immune System Mediators