262
10.7.6.6 TNF-α Inhibitor
TNF-α, a proinflammatory cytokine, is synthesized by activated macrophages and T
cells in human body. Elevated levels of TNF-α and its activation is the root cause of
the development of certain diseases with inflammatory and deregulated immune
response background. Its implication in chronic inflammation and inflammatory
manifestations is previously described. Therefore, inhibition of TNF activation is a
promising therapeutic option (Castro Villegas Mdel et al. 2012). Many approaches
have been developed to inhibit or reduce TNF activity in these disease settings
(Feldmann and Maini 2001). Monoclonal antibodies directed against TNF or its
receptors can inhibit the binding with its receptors and thereby limit TNF-initiated
inflammatory cascade and ameliorate the immune response. Adalimumab,
Infliximab, and Golimumab are anti-TNF-α monoclonal antibody-based drugs, and
etanecept is a soluble TNF-α receptor antagonist (Bell and Kamm 2000; Martorana
et al. 2001; Present et al. 1999). Certolizumab pegol is another TNF-α inhibitor
made of humanized Fab fragment combined with polyethylene glycol (2009;
Schreiber 2007; Smith et al. 2010). However, immunotherapy often suffers from the
potential disadvantage of the necessity of administration at the site of action, wide
range of action, and cost. In addition to protein-based drugs, many natural or synthetic inhibitors of TNF-α are under development. Several biologic drugs have been
developed for treating RA. Another way of inhibiting TNF activity is by inhibiting
the enzyme which forms the mature TNF-α. TNF-converting enzyme plays a pivotal
role in active TNF formation from its inactive form. Active TNF is formed by the
proteolytic cleavage of its inactive form by TNF-α-converting enzyme and so the
enzyme can be another therapeutic target for treatment of RA. TACE inhibitors have
exhibited side effects in clinical trials and so more selective TACE inhibitors have
to be developed. The search for identification of new macrocyclic hydroximates as
selective TACE inhibitors is in progress. Screening for better TACE inhibitors from
natural resources is another sector which needs attention.
10.8 Novel Anti-inflammatory Strategies
New approaches for safer and economic anti-inflammatory drug development are
highly recommended over the currently available drugs which often possess potential side effects. Therefore, novel target identification and validation are mandatory.
Target proteins can be either involved in the biosynthetic regulation of inflammatory
mediators or the proteins involved in the signaling events of inflammation. Many
biologic drugs have been developed for treatment so far, and are an extensive area
of active research. MAPKs (mitogen-activated protein kinases) are a family of serine/threonine protein kinases which mediate biological activities triggered by stress
signals. They are involved in the biosynthesis of many inflammatory mediators,
especially in the synthesis of proinflammatory cytokines. Inhibitors targeting p38
MAPK and JNK pathways have been developed as anti-inflammatory agents, and in
clinical trials in treating chronic inflammatory diseases. The kinase inhibitors of
these proteins can inactivate the downstream events and can also be considered for
B.C. Bhavya and M. Haridas
10.7.6.6 TNF-α Inhibitor
TNF-α, a proinflammatory cytokine, is synthesized by activated macrophages and T
cells in human body. Elevated levels of TNF-α and its activation is the root cause of
the development of certain diseases with inflammatory and deregulated immune
response background. Its implication in chronic inflammation and inflammatory
manifestations is previously described. Therefore, inhibition of TNF activation is a
promising therapeutic option (Castro Villegas Mdel et al. 2012). Many approaches
have been developed to inhibit or reduce TNF activity in these disease settings
(Feldmann and Maini 2001). Monoclonal antibodies directed against TNF or its
receptors can inhibit the binding with its receptors and thereby limit TNF-initiated
inflammatory cascade and ameliorate the immune response. Adalimumab,
Infliximab, and Golimumab are anti-TNF-α monoclonal antibody-based drugs, and
etanecept is a soluble TNF-α receptor antagonist (Bell and Kamm 2000; Martorana
et al. 2001; Present et al. 1999). Certolizumab pegol is another TNF-α inhibitor
made of humanized Fab fragment combined with polyethylene glycol (2009;
Schreiber 2007; Smith et al. 2010). However, immunotherapy often suffers from the
potential disadvantage of the necessity of administration at the site of action, wide
range of action, and cost. In addition to protein-based drugs, many natural or synthetic inhibitors of TNF-α are under development. Several biologic drugs have been
developed for treating RA. Another way of inhibiting TNF activity is by inhibiting
the enzyme which forms the mature TNF-α. TNF-converting enzyme plays a pivotal
role in active TNF formation from its inactive form. Active TNF is formed by the
proteolytic cleavage of its inactive form by TNF-α-converting enzyme and so the
enzyme can be another therapeutic target for treatment of RA. TACE inhibitors have
exhibited side effects in clinical trials and so more selective TACE inhibitors have
to be developed. The search for identification of new macrocyclic hydroximates as
selective TACE inhibitors is in progress. Screening for better TACE inhibitors from
natural resources is another sector which needs attention.
10.8 Novel Anti-inflammatory Strategies
New approaches for safer and economic anti-inflammatory drug development are
highly recommended over the currently available drugs which often possess potential side effects. Therefore, novel target identification and validation are mandatory.
Target proteins can be either involved in the biosynthetic regulation of inflammatory
mediators or the proteins involved in the signaling events of inflammation. Many
biologic drugs have been developed for treatment so far, and are an extensive area
of active research. MAPKs (mitogen-activated protein kinases) are a family of serine/threonine protein kinases which mediate biological activities triggered by stress
signals. They are involved in the biosynthesis of many inflammatory mediators,
especially in the synthesis of proinflammatory cytokines. Inhibitors targeting p38
MAPK and JNK pathways have been developed as anti-inflammatory agents, and in
clinical trials in treating chronic inflammatory diseases. The kinase inhibitors of
these proteins can inactivate the downstream events and can also be considered for
B.C. Bhavya and M. Haridas