260
a variety of transcription factors like ATF-2, Elk1, NFκB, TRAF6, and STAT
involved in the synthesis and release of many proinflammatory cytokines, which
further accelerate the inflammatory cascade. Thus the inhibition of these cytokines
can be achieved via three basic strategies: antibodies or small-molecule ligands
against cytokines or to their specific receptors, small-molecule inhibitors which
either target regulatory site on protein or active site of enzyme or the receptor, and
targeting the molecules involved in cytokine synthesis and signaling pathways
(interleukin or TNF-converting enzymes, MAPKs) (Arend 2002).
10.7.6.1 IL-1 Inhibitor
Interleukin-1 (IL-1) inhibitors possess anti-inflammatory and immunomodulatory
actions. They are found promising in managing refractory gout or for patients who
are unable to tolerate conventional NSAIDs, colchicine, or glucocorticoids. IL-1
inhibitors are used against a variety of autoinflammatory diseases. The IL-1 inhibitors used in gout include anakinra, canakinumab, and rilonacept (Camp et al. 2005;
Morton et al. 2005; Somm et al. 2006). Anakinra is such peptidyl drug synthesized
as a recombinant protein of IL-1 receptor antagonists for treating RA. Anakinra
inhibits the binding of IL-1 to both IL-1RI and IL-1RII with high affinity competitively thus preventing the IL-1from binding with the receptors. Interleukin inhibitors can also serve as immunosuppressive agents (Clark et al. 2004; de La Mata
et al. 2007; Waugh and Perry 2005).
10.7.6.2 IL-6 Inhibitors
IL-6 has been found to play a crucial role in the pathogenesis of RA and a viable
target for autoimmune diseases. Inhibitors of IL-6 were found promising in in vivo
models of autoimmune disease. Tocilizumab, a humanized monoclonal antibody
specific for the IL-6 receptor, has been developed for treating RA (Patel and
Moreland 2010; Van Snick 1990).
10.7.6.3 IL-17 Inhibitor
IL-17 overproduction and hyperactivity is directly correlated with the pathophysiology of many autoimmune and inflammatory disorders such as plaque psoriasis.
IL-17 blocker seems to regulate immune response underlying psoriasis. Cosentyx is
the first IL-17 inhibitor approved for different levels of psoriasis (Leonardi et al.
2012; Moseley et al. 2003).
10.7.6.4 ICE Inhibitors
IL1α and IL1β represent the isoforms of IL-1. IL1β is expressed in inactive form
and IL1β converting enzyme (caspase 1) converts it into its active form by inducing
proteolytic cleavage at Asp116-Ala117. This step is rate limiting and hence ICE is
regarded as a potent target for therapeutic exploitation to limit interleukin-mediated
inflammation. Many ICE inhibitors have been developed as anti-inflammatory or
immune response-regulating agents based on this concept. Several peptides and
nonpeptide ICE inhibitors were synthesized (Okamoto et al. 1999; Shahripour et al.
2002; Vezzani et al. 2010). The peptidomimetic ICE inhibitors were developed from
B.C. Bhavya and M. Haridas
a variety of transcription factors like ATF-2, Elk1, NFκB, TRAF6, and STAT
involved in the synthesis and release of many proinflammatory cytokines, which
further accelerate the inflammatory cascade. Thus the inhibition of these cytokines
can be achieved via three basic strategies: antibodies or small-molecule ligands
against cytokines or to their specific receptors, small-molecule inhibitors which
either target regulatory site on protein or active site of enzyme or the receptor, and
targeting the molecules involved in cytokine synthesis and signaling pathways
(interleukin or TNF-converting enzymes, MAPKs) (Arend 2002).
10.7.6.1 IL-1 Inhibitor
Interleukin-1 (IL-1) inhibitors possess anti-inflammatory and immunomodulatory
actions. They are found promising in managing refractory gout or for patients who
are unable to tolerate conventional NSAIDs, colchicine, or glucocorticoids. IL-1
inhibitors are used against a variety of autoinflammatory diseases. The IL-1 inhibitors used in gout include anakinra, canakinumab, and rilonacept (Camp et al. 2005;
Morton et al. 2005; Somm et al. 2006). Anakinra is such peptidyl drug synthesized
as a recombinant protein of IL-1 receptor antagonists for treating RA. Anakinra
inhibits the binding of IL-1 to both IL-1RI and IL-1RII with high affinity competitively thus preventing the IL-1from binding with the receptors. Interleukin inhibitors can also serve as immunosuppressive agents (Clark et al. 2004; de La Mata
et al. 2007; Waugh and Perry 2005).
10.7.6.2 IL-6 Inhibitors
IL-6 has been found to play a crucial role in the pathogenesis of RA and a viable
target for autoimmune diseases. Inhibitors of IL-6 were found promising in in vivo
models of autoimmune disease. Tocilizumab, a humanized monoclonal antibody
specific for the IL-6 receptor, has been developed for treating RA (Patel and
Moreland 2010; Van Snick 1990).
10.7.6.3 IL-17 Inhibitor
IL-17 overproduction and hyperactivity is directly correlated with the pathophysiology of many autoimmune and inflammatory disorders such as plaque psoriasis.
IL-17 blocker seems to regulate immune response underlying psoriasis. Cosentyx is
the first IL-17 inhibitor approved for different levels of psoriasis (Leonardi et al.
2012; Moseley et al. 2003).
10.7.6.4 ICE Inhibitors
IL1α and IL1β represent the isoforms of IL-1. IL1β is expressed in inactive form
and IL1β converting enzyme (caspase 1) converts it into its active form by inducing
proteolytic cleavage at Asp116-Ala117. This step is rate limiting and hence ICE is
regarded as a potent target for therapeutic exploitation to limit interleukin-mediated
inflammation. Many ICE inhibitors have been developed as anti-inflammatory or
immune response-regulating agents based on this concept. Several peptides and
nonpeptide ICE inhibitors were synthesized (Okamoto et al. 1999; Shahripour et al.
2002; Vezzani et al. 2010). The peptidomimetic ICE inhibitors were developed from
B.C. Bhavya and M. Haridas