Emerging targets for novel therapy of asthma

Abstract

Significant advances in understanding the cell and molecular biology of inflammation and airway smooth muscle (ASM) contractility have identified several potential novel targets for therapies of asthma. New agents targeting G-protein coupled receptors (GPCRs) including bitter taste receptors (TAS2R) agonists and prostaglandin EP4 receptor agonists elicit ASM relaxation. The cAMP/PKA pathway continues to be a promising drug target with the emergence of new PDE inhibitors and a novel PKA target protein, HSP20, which mediates smooth muscle relaxation via actin depolymerization. Smooth muscle relaxation can also be elicited by inhibitors of the RhoA/Rho kinase pathway via inhibition of myosin light chain phosphorylation and actin depolymerization. Targeting epigenetic processes that control chromatin remodeling and RNA-induced gene silencing in airway cells also holds great potential for novel asthma therapy. Further investigation may identify agents that inhibit smooth muscle contraction and/or restrain or reverse obstructive remodeling of the airways.

Figure 1. Proposed mechanisms of smooth muscle relaxation by activation of bitter taste (TAS2R) and prostaglandin E (EP4) receptors in human airway smooth muscle

TAS2R activation may produce relaxation by activating BK channels to produce hyperpolarization and decreases calcium concentration in limited regions of the cell. Activation of EP2 and EP4 receptors elicit airway smooth relaxation by Gs coupled activation of adenylate cyclase (AC), production of cAMP and activation of protein kinase A (PKA), which phosphorylates multiple substrates to decrease cell calcium concentration. Decreasing calcium reduces activation of myosin light chain kinase (MLCK) thus favoring myosin light chain dephosphorylation by myosin phosphatase (subunits PP1c, MYPT and M20). Dephosphorylation of myosin results in relaxation.

Figure 2. Mechanisms of bronchodilation by phosphorylation of HSP20 and inhibition of Rho kinases

Beta adrenergic agonists act by multiple mechanisms to relax airway smooth muscle including decreasing cell calcium oscillations by reducing calcium entry (not shown), increasing calcium uptake into the sarcoplasmic reticulum (SR), activating myosin phosphatase (subunits PP1c, MYPT, M20) and by phosphorylating HSP20. HSP20 may have multiple effects on the contractile filaments including an indirect effect on activation of the slingshot phosphatase which dephosphorylates cofilin. Dephosphorylated cofilin binds Factin filaments and promotes depolymerization to G-actin and relaxation. Rho kinase inhibitors enhance the activity of myosin phosphatase (PP1c) to favor dephosphorylated myosin light chains which results in smooth muscle relaxation. Statins inhibit prenylation of small G proteins, including RhoA, which inhibits the Rho/Rho kinase pathway.

Figure 3. Epigenetic mechanisms that are targets for new drug development in lung diseases

A. The histone code represented here as histone acetylation (Ac) and methylation (Me) controls condensation and relaxation of chromatin. Relaxed chromatin enhances mRNA synthesis and expression of proteins. Histone modifying enzymes, including histone deacetylases, acetyltransferases, demethylases and methyl transferases are emerging targets for small molecule inhibitors that alter expression of pro-inflammatory genes and genes involved in hyperplasia and hypertrophy of various airway cells. B. MicroRNA gene silencing via translational block and mRNA destabilization controls protein abundance. miRNA antagonists inhibit the function of endogenous miRNAs, probably by hybridizing with the endogenous miRNA. This approach is being developed to antagonize protein expression networks that contribute to inflammation and airway hyperreactivity.