Syk inhibitors as treatment for allergic rhinitis
Section snippets
IgE and allergic rhinitis pathophysiology
Allergic rhinitis is caused by an overzealous immune response to allergens leading to rapid nasal-ocular symptoms, which include runny nose, itching, sneezing, and nasal congestion. In addition to the early symptoms, late responses to recurring challenges with allergen can also lead to local inflammation resulting in a “primed” nasal mucosa that becomes hyper-responsive to smaller amounts of antigens or to other non-specific triggers. The initial triggers for allergic rhinitis can be seasonal,
From allergic mediators to medications
Treatment options for allergic rhinitis include allergen avoidance, which is frequently impractical [9], [10]. Another therapeutic strategy has been allergen-specific immunotherapy with the aim to alter and blunt immune responses to the particular noxious allergens. However, immuno-modulation therapies to desensitize patients are complex, time consuming, and are still being optimized [11], [12].
More common are medications targeting or antagonizing the production or action of the mediators
Targeting IgE and FcεRI signaling
Rather than antagonizing single mediators, an alternative approach is to inhibit the production and release of all mast cell mediators by antagonizing IgE action. In this respect, an important addition to drug therapies for allergic conditions is the antibody omalizumab, which recognizes and neutralizes IgE [5], [18]. Systemic treatment with omalizumab causes the reduction of IgE levels in the serum and the subsequent downregulation of FcεRI expression on the cell surface of mast cells and
Syk as a target for FcεRI signaling inhibition
Syk, also known as spleen tyrosine kinase, is a 72 kDa non-receptor kinase of the ZAP70/Syk family of tyrosine kinases. Syk is expressed in most, if not all, hematopoietic cells and is best known for its critical role in immunoreceptor signaling through the common ITAM motifs found in the cytoplasmic domains of Fc and antigen receptors [22], [30], [31]. These receptors mediate immunoglobulin or antigen binding and cellular activation in a variety of hematopoietic cells. While ZAP70 is
Inhibitors of Syk gene expression and Syk kinase activity
Two main approaches have been undertaken in the search for Syk inhibitors for therapeutic purposes: suppression of Syk gene expression using antisense oligonucleotides to Syk mRNA (Syk-ASO) and inhibition of Syk kinase activity using small molecules.
Topical delivery into rat airways of a 60-nucleotide Syk-ASO, modified with phosphothioate for increased stability and formulated as an aerosolized liposome complex, resulted in alveolar macrophages with remarkably reduced Syk protein expression [40]
Blocking FcεRI signaling to find Syk inhibitors
The classical biochemical approach, although simple and direct, suffers from the fact that biochemical assays do not always faithfully mimic the native state of the enzyme in its intracellular context. Furthermore, with regards to biochemical kinase selectivity, it is interesting to note that the significance of wide-ranging biochemical kinase profiling has been questioned since some drugs have shown acceptable safety profiles despite significant activity in large number of kinases [48]. An
Syk inhibitors in clinical studies of allergic rhinitis
R112 exhibited suitable properties for topical intranasal delivery. A stable suspension formulation of R112 was developed and can be administered using metered spray pumps. In addition, R112 is rapidly metabolized as it enters the systemic circulation, allowing for high local concentration of the drug with minimal systemic exposures. A nasal allergen challenge study demonstrated R112 safety and mediator release inhibition [50]. Particularly interesting was the statistically significant
Concluding comments
Extensive studies have cemented the central role for IgE and mast cells in allergic rhinitis. Syk kinase inhibition, by blocking IgE–FcεRI receptor signaling in mast cells, then represents an appealing strategy for the discovery of new type of allergic rhinitis medications. Syk kinase inhibitors effects go beyond mast cells as they also inhibit activation of other cellular components of the inflammatory cascade induced by specific antigen and immunoglobulin. These inhibitors thus offer much
Acknowledgments
We thank Donald G. Payan, Elliott Grossbard and members of the mast cell and Syk projects at Rigel for critical reading of the manuscript and helpful discussions.
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2017, European Journal of PharmacologyCitation Excerpt :These mediators cause various reactions such as vasodilation, vascular hyperpermeability, edema, mucus hypersecretion, smooth muscle contraction, pain, pruritus, cell infiltration, and tissue destruction (Abbas et al., 2000; Hein, 2002; Masuda and Schmitz, 2008; Rolin et al., 2006; Undem and Taylor-Clark, 2014). This indicates that the mediators derived from mast cells with IgE-crosslinking play important roles in pathogenesis of allergic diseases like urticaria, asthma, and allergic rhinitis (Masuda and Schmitz, 2008; Rossi et al., 2006). In fact, some conventional drugs which target the mediators are clinically used for allergic diseases (Masuda and Schmitz, 2008; Rossi et al., 2006).