The bane of many modern drugs is undesirable side effects. Now, a team of researchers from the Indian Institute of Technology Kanpur (IITK), working closely with its counterparts at Cambridge, may have found a way to rid life-saving medicines of side effects.
For the work, published in the prestigious journal Nature on Wednesday, the researchers, led by Arun K Shukla, a Joy Gill Chair Professor, at IITK’s Department of Biological Sciences and Bioengineering, and Christopher Tate of the MRC Laboratory of Molecular Biology at Cambridge, used a commonly used asthma drug, formoterol.
Using powerful cryogenic electron microscopy, the scientists managed to capture how formoterol binds with its receptor on the cell surface and turns it on.
Formoterol is a drug commonly used to treat asthma and other respiratory illnesses. In people suffering from asthma, the airways are inflamed and become narrow which, in turn, makes breathing difficult. A bronchodilator, formoterol relaxes the smooth muscle present in the airways and thus makes breathing easy for the patients. However, some of the side effects associated with formoterol include dizziness, nausea and throat irritation.
Formoterol works by activating a specific type of proteins called beta-adrenergic receptors present in the cells of airway smooth muscle. These receptors belong to a large family of proteins — G protein-coupled receptors (GPCRs) — that sit on the surface of every living cell.
These receptors are at the centre of every physiological process in our body. We see things when light particles fall on rhodopsin molecules — GPCR — in the retina, we get to smell when the receptors in nostril cells get activated, and we flee when an impending danger approaches us as GPCRs in different types of cells receive chemical cues in the form of hormones, prompting different organs to act appropriately.
These receptors also regulate everything from heartbeats to immune response. Significantly, about half of the currently prescribed medicines work by activating or inactivating one of these receptors in our body.
Significant discovery
In the present study, the researchers managed to capture and visualise the drug-receptor complex of formoterol and beta-adrenergic receptor, together with a protein called beta-arrestin, which mediates the cellular response triggered by their binding.
Since such protein complexes are generally very short-lived in cells, the scientists used a synthetic antibody fragment against beta-arrestin to lock the entire complex together and then examined it under the microscope. The availability of this structure allows scientists to better understand how this particular drug acts on the receptor and activates the downstream signalling pathways that result in relief from asthma symptoms.
Till almost a decade ago, scientists had thought that GPCRs worked only through one class of proteins present in the cell called G proteins. Soon, this understanding changed when scientists discovered yet another signalling pathway, which worked through beta-arrestin. Beta-arrestin was earlier known only as a “switch” that turned off the G protein function.
Explaining it, Shukla said one of these signalling pathways produced beneficial effects, while the other triggered side effects. If scientists know which was desirable, they could try to stop or minimise the mechanism by the other.
In the past two decades, the focus of GPCR targeting medicines has shifted to leverage this new paradigm in order to reduce the side effects of current drugs. The study by Shukla and his team now provides a major breakthrough towards this ambitious goal.
Going forward, the authors plan to visualise similar complexes of other receptors involved in various human diseases such as inflammatory disorders, Parkinson’s disease, obesity, heart failure and cancer. These studies are likely to help better understand the inner workings of this important class of drug targets and, thereby, open novel avenues to design drugs that are more efficient, safe, and cause fewer side effects.