Bitter Taste Receptors for Asthma Therapeutics

Abstract

Clinical management of asthma and chronic obstructive pulmonary disease (COPD) has primarily relied on the use of beta 2 adrenergic receptor agonists (bronchodilators) and corticosteroids, and more recently, monoclonal antibody therapies (biologics) targeting specific cytokines and their functions. Although these approaches provide relief from exacerbations, questions remain on their long-term efficacy and safety. Furthermore, current therapeutics do not address progressive airway remodeling (AR), a key pathological feature of severe obstructive lung disease. Strikingly, agonists of the bitter taste receptors (TAS2Rs) deliver robust bronchodilation, curtail allergen-induced inflammatory responses in the airways and regulate airway smooth muscle (ASM) cell proliferation and mitigate features of AR in vitro and in animal models. The scope of this review is to provide a comprehensive and systematic insight into our current understanding of TAS2Rs with an emphasis on the molecular events that ensue TAS2R activation in distinct airway cell types and expand on the pleiotropic effects of TAS2R targeting in mitigating various pathological features of obstructive lung diseases. Finally, we will discuss specific opportunities that could help the development of selective agonists for specific TAS2R subtypes in the treatment of asthma.

Airway Remodeling in Asthma

“…Agonists of the bitter taste receptors (TAS2Rs) promote bronchodilation, restrict allergen-induced inflammatory responses, and ASM proliferation and mitigate features of airway reactivity in vitro and in animal models (169,170). Increased sphingosine kinase 2 (SPHK2) levels in proliferating ASM cells may be exploited to alleviate airway smooth muscle thickening with synthetic substrates (171,172). When bronchodilatory responses to β-receptor agonists are blunted, the synthetic peroxisome proliferator activated receptor (PPAR)-γ agonist, rosiglitazone, may have benefit in eliciting ASM relaxation in ex vivo mouse lung slice models (173).…”

Clinical Role of Extraoral Bitter Taste Receptors

“…One of the many challenging aspects in the development of TAS2Rs as therapeutic targets is the dearth of receptor subtype-specific agonists with a refined pharmacological profile. Although there are well-characterised bitter compounds at our disposal, agonist-receptor subtype promiscuity has forestalled progression to clinical trials [ 91 , 92 ].…”

Structure-Function Analyses of Human Bitter Taste Receptors—Where Do We Stand?

“…Since TAS2Rs were not considered as relevant drug targets until very recently, one could imagine that these receptors were not ranked as a top priority for such kind of analyses. The findings that some bitter compounds represent highly efficient drugs for asthma treatment [ 74 ] may serve as alternative anti-diabetic drugs [ 75 ], and could even become relevant for the treatment of cancer [ 76 ], may result in a shift of priorities.…”