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Identifying Molecular Targets for New Drug Development for Chronic Obstructive Pulmonary Disease: What Does the
1National Heart and Lung Institute, Imperial College London, London, United Kingdom.
Abstract:
There is an urgent need to develop more effective therapies for chronic obstructive pulmonary disease (COPD) that target the underlying inflammatory disease process. Current therapies with long-acting bronchodilators and inhaled corticosteroids fail to prevent either disease progression or mortality, as they do not suppress the underlying inflammation. With better understanding of the inflammatory and destructive process in the pathophysiology of COPD, several new therapeutic targets have been identified. Several mediator antagonists or inhibitors tested in COPD have so far been disappointing. Broad-spectrum anti-inflammatory drugs may be more effective, and include inhibitors of the proinflammatory enzymes phosphodiesterase-4, p38 mitogen-activated protein kinase, Janus-activated kinases, NF-κB kinase, and PI3kinase-γ and -δ, but side effects after oral administration are a major limitation; therefore, in future inhaled delivery may be necessary. A new promising approach is reversal of corticosteroid resistance through increasing histone deacetylase-2 activity. This might be achieved by existing treatments such as theophylline, nortriptyline, and macrolides, or more selectively by PI3kinase-δ inhibitors. Other treatments in development target oxidative stress, the failure to resolve inflammation, aberrant repair mechanisms, and accelerated lung aging.
Insights
New therapies are needed for chronic obstructive pulmonary disease (COPD) as current treatments do not address underlying inflammation. Promising approaches include broad-spectrum anti-inflammatory drugs and reversing corticosteroid resistance.
Area of Science:
- Pulmonary Medicine
- Inflammation Research
- Pharmacology
Background:
- Chronic obstructive pulmonary disease (COPD) therapies, including bronchodilators and corticosteroids, are insufficient as they do not target the core inflammatory process.
- This leads to continued disease progression and mortality, highlighting the need for novel therapeutic strategies.
Purpose of the Study:
- To review emerging therapeutic targets and strategies for COPD that address the underlying inflammatory pathophysiology.
- To evaluate the potential of broad-spectrum anti-inflammatory agents and methods to overcome corticosteroid resistance.
Main Methods:
- Review of current literature on COPD pathophysiology and therapeutic targets.
- Analysis of novel drug classes targeting inflammatory pathways such as phosphodiesterase-4, p38 MAPK, JAK, NF-κB, and PI3K.
- Exploration of strategies to reverse corticosteroid resistance, including histone deacetylase-2 activation.
Main Results:
- Many targeted mediator antagonists have shown disappointing results in COPD.
- Broad-spectrum anti-inflammatory drugs targeting enzymes like PDE4, p38 MAPK, JAK, NF-κB, and PI3K show promise but face oral administration side effects.
- Reversing corticosteroid resistance via HDAC2 activation, potentially with theophylline, macrolides, or PI3K-δ inhibitors, is a promising avenue.
Conclusions:
- Novel COPD therapies must target the underlying inflammation and potentially overcome corticosteroid resistance.
- Inhaled delivery may mitigate side effects of systemic anti-inflammatory drugs.
- Future treatments will likely focus on inflammation, oxidative stress, resolution of inflammation, repair mechanisms, and lung aging.
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