Pepducins as a potential treatment strategy for asthma and COPD

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Current therapies to treat asthma and other airway diseases primarily include anti-inflammatory agents and bronchodilators. Anti-inflammatory agents target trafficking and resident immunocytes and structural cells, while bronchodilators act to prevent or reverse shortening of airway smooth muscle (ASM), the pivotal tissue regulating bronchomotor tone. Advances in our understanding of the biology of G protein-coupled receptors (GPCRs) and biased agonism offers unique opportunities to modulate GPCR function that include the use of pepducins and allosteric modulators. Recent evidence suggests that small molecule inhibitors of Gαq as well as pepducins targeting Gq-coupled receptors can broadly inhibit contractile agonist-induced ASM function. Given these advances, new therapeutic approaches can be leveraged to diminish the global rise in morbidity and mortality associated with asthma and chronic obstructive pulmonary disease.

Introduction

Profound advances in the fields of receptor biology and pharmacology have now identified novel approaches to modulate the function of G protein-coupled receptors (GPCRs), the largest super family of cell-surface receptors in the human genome [1, 2]. Although the concept of rational drug design has existed for decades, only recently have structural biology and molecular modeling capabilities advanced this concept beyond the theoretical stage. Providing a further boost is the related and exploding field of biased ligand pharmacology, whose insights have greatly advanced our understanding of qualitative GPCR signaling. One intriguing discovery 16 years ago was the identification that receptor intracellular surface loops that interact with G proteins can be targeted by N-terminal lipidated peptides (pepducins) to modulate GPCR signaling and potentially serve as therapeutics [1, 3].

Current therapies to treat asthma and other airway diseases primarily include anti-inflammatory agents and bronchodilators. Anti-inflammatory agents target trafficking and resident immunocytes and structural cells, while bronchodilators act to prevent or reverse shortening of airway smooth muscle (ASM), the pivotal tissue regulating bronchomotor tone. Unfortunately, about 50% of patients with asthma have inadequate control with current therapeutics [4]. Despite some refinements in the duration and specificity of β2-adrenergic receptor (β2AR) agonists and in the use of antagonists of contractile GPCRs in asthma, continued refinement may yield diminishing returns and truly novel approaches will be needed to overcome current limitations and address the needs of patients not served by currently available therapies.

Most bronchodilators are GPCR ligands which exert their action by either promoting pro-relaxant or inhibiting pro-contractile signaling. This underscores the importance of the competitive balance of pro-relaxant and pro-contractile GPCR signaling in regulating ASM contractility and airway resistance in obstructive lung diseases [5, 6, 7]. Airway resistance is also affected by structural changes in the airways (airway remodeling) and pulmonary architecture as well as tissue mechanics, but GPCR ligands acting on ASM have the strongest impact on changes in airflow.

Increased levels of endogenous contractile GPCR agonists have been associated with allergic airway inflammation, leading to increased ASM contraction and airflow obstruction. One strategy to ameliorate this is to inhibit pro-contractile GPCR signaling by administering a small molecule antagonist of a pro-contractile receptor. This approach may be suboptimal or entirely ineffective when multiple GPCRs are activated to contract ASM. Treatment with β-agonists relaxes airways by antagonizing pro-contractile GPCRs at several loci in airway smooth muscle including transmembrane receptor signaling, calcium mobilization and flux, and distal regulation of contractile filaments through regulation of myosin light chain kinase/phosphatase (MLCK/MLCP) activity. Therefore, use of β-agonists has an inherent advantage over selective antagonists of pro-contractile GPCRs as β-agonists dilate/protect airways irrespective of the type of pro-contractile stimulus. Even though inhaled β-agonists are the mainstay therapy for acute bronchospasm and combined long-acting β-agonist (LABA) and corticosteroid treatment is the cornerstone of asthma and chronic obstructive pulmonary disease (COPD) maintenance therapy, concerns about β-agonist efficacy and safety have persisted for decades. Chronic β-agonist use has been associated with β2AR tachyphylaxis [8, 9, 10], loss of asthma control [11, 12, 13], and death [14, 15, 16, 17]. Although associations of chronic β-agonist use with adverse events have not been uniquely observed in all studies [18, 19, 20], the need for understanding mechanisms involved in detrimental effects of β-agonists on lung physiology and pathology remains.

Fortunately, recent basic science research in GPCR biology and pharmacology has discovered novel modes of GPCR signaling and regulation that potentially explains the complex effects of existing drugs while offering the promise of new, more efficacious drugs. In this review, we summarize studies based on newfound paradigms in GPCR biology to (1) identify strategies capable of making existing asthma and COPD drugs better; and (2) develop new drugs that work by distinctly different mechanisms.

Section snippets

Diverse receptor conformations are linked to differential signaling events; arrestins and biased ligands can influence the qualitative nature of signaling

GPCR ligands are often characterized based on their efficacy, be it positive or negative, to a specific signaling pathway that is in turn linked to a specific cellular function. However, it has been apparent for some time that there exists a much greater complexity of ligand-receptor interactions, and recent studies that attempt to explain ‘why’ are probably only scratching the surface of the regulatory phenomena that enable receptor dexterity. Numerous GPCRs exhibit significant diversity in

Novel strategies co-opting heterotrimeric G protein regulatory mechanisms can regulate ASM contraction

GPCRs in ASM represent attractive therapeutic targets for multiple reasons, including the ability to readily target them with selective agents (inhaled small molecules). Approaches for targeting downstream elements have some conceptual appeal; for example, broad-based strategies for inhibiting the heterotrimeric Gq protein could be an effective means of negating the effects of all pro-contractile agonists in the inflamed airway, and overcoming the limitations of monotherapies such as tiotropium

Summary

Despite considerable research efforts, asthma and COPD remain substantial therapeutic challenges and contribute globally to increasing morbidity and mortality. Bronchodilators reverse or prevent shortening of airway smooth muscle, and remain principal drugs in both prophylactic management and treatment of obstructive airway diseases. Over the past two decades, advances in management of the non-severe asthma/COPD patient have been limited to modest refinements in traditional bronchodilator

Funding sources

NIH/NHLBI, 1P01-HL114471-01A1.

Conflict of interest statement

Nothing declared.

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