How often do you bring your attention to your breath? For most people, it is largely a subconscious act; something so significant and yet we are hardly aware of it. But for many, every inhalation is a constant battle. Diseases like asthma and cystic fibrosis can reduce people to gasping, feeling like fish out of water. Fortunately the invention of drugs, like inhaled glucocorticoids, has been life changing for many sufferers of respiratory disease, helping those to control their symptoms and allow for a more normal, active life.
Under the burden
The word "asthma" originates from the Greek word meaning ‘short of breath�. Asthma often begins in childhood and is the most common long term chronic condition that continues through to adulthood. The airways in the lungs become narrow, swollen and produce extra mucus making it harder to breathe. Symptoms can vary, including coughing, wheezing, shortness of breath and chest tightness, and range from mild to severe, occurring frequently or occasionally. Both genetic and environmental factors, like cold air, pollution and allergens, can trigger the onset or worsen the symptoms leading to what is called an asthma attack. Currently there is no cure for asthma but with improved diagnosis, treatment, and monitoring, this long term condition can be managed well to keep the symptoms under control.
Powerful glucocorticoids
Our body naturally produces glucocorticoids, a class of steroid hormone secreted by the adrenal gland, in response to stress. Glucocorticoids being lipophilic in lipids cross the cell membrane and bind its cytoplasmic and ubiquitously expressed glucocorticoid receptor. The complex then moves to the nucleus where it acts as a transcription factor to affect the transcription of genes involved in diverse functions.
Glucocorticoid receptor is composed of three major functional domains, namely the N-terminal transactivation domain, the central DNA-binding domain, and the C-terminal ligand-binding domain. There are 50 structures of glucocorticoid receptors present in the PDB that can be explored at the PDBe-KB protein pages. They interact with DNA, transcription co-activators and heat shock proteins (among others) that control many distinct gene networks, each uniquely determined by a specific cellular and physiological factor.
Ligand (glucocorticoid) binding induces conformational changes within the receptor, resulting in subsequent binding of the specific DNA regions, to activate or repress target gene expression. The changes in receptors caused by glucocorticoids are essential for the use of carbohydrate, fat and protein by the body and therefore glucocorticoids can affect the brain function to influence mood, behaviour, cognition, memory and sleep cycles.
Glucocorticoids are best known for their ability to suppress inflammation. They increase the expression of anti-inflammatory proteins in the nucleus that downregulate and repress the production and release of pro-inflammatory cytokines and other proteins. In addition, glucocorticoids prevent damage caused by several autoimmune diseases where the body mistakenly attacks itself, like multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease. They suppress inflammation, reduce pain, swelling and cramping caused by these autoimmune reactions.
Man-made glucocorticoids
Given the broad physiological and therapeutic effects of glucocorticoids, several synthetic versions of these steroid hormones have been developed, often called corticosteroids. From the discovery of glucocorticoids to the present day, they are considered to be the most effective anti-inflammatory drugs, as well as the most widely prescribed drug classes worldwide. These include dexamethasone (DEX), hydrocortisone (HCY) or cortisol, prednisolone, beclomethasone, and many more. The most common, hydrocortisone, its single shot can help ease inflamed joints and reduce pain in arthritis. Prednisone is another such glucocorticoid that is metabolised by the liver to its active form, prednisolone (PDN), used in treatment to suppress the immune system and decrease inflammation in conditions such as asthma. Dexamethasone treatment proved to be an inexpensive way to treat COVID-19 and has saved millions of lives worldwide.
Structure clusters representing all superimposed ligands for human Glucocorticoid receptor (UNP id P04150),showing ligand binding domain with glucocorticoids like dexamethasone (DEX), hydrocortisone (HCY), mometasone furoate (MOF), fluticasone furoate (GW6), Mifepristone (486) and many more.
Life saving inhalers
Sir David Jack FRS, former Director at Glaxo, specialised in the development of several drugs for treating asthma. He recognized the importance of delivering drugs directly to lungs by inhalation, in order to gain a more rapid response that would in turn reduce systemic side effects. He was best known for his discovery of the first β2-selective agonist salbutamol (68H). Salbutamol (brand name - Ventolin®), causes smooth muscle relaxation and dilatation of the airways that provides fast and effective relief when asthma is triggered. This proved to be a major commercial success and remains the most widely used asthma drug in the world today. However, given its short duration of action of just 4 hours, it has to be used more frequently. He discovered salmeterol (Serevent®) (), the first long-acting β2-agonist with a longer duration of 12 hours.
![image](/pdbe/sites/ebi.ac.uk.pdbe/files/documents/salbu%20salm_0.png")
Salbutamol () and salmeterol (), the two smooth muscle relaxants bound to beta2 adrenergic receptor shown in ball and stick form on the top and bottom respectively.
Oral corticosteroids were very effective in asthma treatment but could not be used routinely due to long-term side effects. This led Sir David’s team to develop the first inhaled steroids, beclomethasone dipropionate (Becotide®), used in the long-term management of asthma. This revolutionised the therapy of asthma, cutting down asthma exacerbations, preventing hospital admissions and reducing mortality.
![image](/pdbe/sites/ebi.ac.uk.pdbe/files/documents/3CLD_1_0_0_0_0.png")
Fluticasone propionate (PDB ID ), a potent inhaled corticosteroids found in nasal sprays to relieve asthma and nasal inflammation, shown here in ball and stick representation, complexed with glucocorticoid receptor.
His team also developed the most widely used inhaled corticosteroid - fluticasone propionate (Flixotide®), PDB ID , which is more potent than beclomethasone dipropionate. Clinical studies showed that when salmeterol was added to fluticasone propionate it improved asthma control to a greater extent than increasing the dose of a single type of inhaled corticosteroids. This led to the development of a combination inhaler (Seretide) launched in 2000 that became the third best selling drug in the world.
Deepti Gupta
About the artwork
Inhalers have been widely used to treat asthma and chronic obstructive pulmonary disease. Even today this is one of the first, and most effective choices to inhibit bronchial inflammation and improve lung function that opens up the airways and helps ease asthma symptoms, allowing people with asthma to have better control over their condition. This artwork from Wendy Wu of The Leys School, Cambridge, features an artistic impression of lungs combined with the glucocorticoid receptor protein.
View the artwork in the .
Structures mentioned in this article -
Link to glucocorticoid receptor protein at the PDBe-KB protein pages
Link to glucocorticoids - dexamethasone (DEX), hydrocortisone (HCY), prednisolone (PDN), mometasone furoate (MOF), fluticasone furoate (GW6), mifepristone (486)
Link to salbutamol (68H), salmeterol (), fluticasone propionate (GW6)
Link to the PDB ID for the entries - , ,
Sources -
. Edman K, Ahlgren R, Bengtsson M, et al. Bioorg Med Chem Lett. 2014;24(11):2571-2577. PMID: 24755427.
Alexaki VI, Henneicke H. Horm Metab Res. 2021 Jan;53(1) 9-15. doi:10.1055/a-1300-2550. PMID: 33207372; PMCID: PMC7781662.
Ciato D, Albani A. Frontiers in Endocrinology. 2020 ;11:21. DOI: 10.3389/fendo.2020.00021. PMID: 32117053; PMCID: PMC7025590.
. Page, Clive, and Patrick Humphrey. British journal of clinical pharmacology vol. 75,5 (2013): 1213-8. PMID: 22994263; PMCID: PMC3635591
