'Dimmer switch' medicines: a revolution in treatment with fewer side effects

By targeting previously unappreciated drug recognition sites in the body, a new class of medicine is on the horizon that will effectively treat chronic conditions while being selective enough to eliminate side effects.

Professor Arthur Christopoulos and Professor Patrick Sexton from Monash University are world leaders in the study of G protein-coupled receptors (GPCRs) and the application of analytical pharmacology to understand allosteric modulation. In recent years, their work has challenged traditional views of how medicines were thought to work.

Their research into GPCRs, the largest class of drug targets, has begun to unravel the complexities of drug action that could lead to more targeted medicines. According to the researchers, medicines that can be ‘turned up’ or ‘turned down’ will give doctors more variability to tailor treatment to the patient’s medical needs. Medicines based on this ‘dimmer switch’ principle will allow patients to lead a more normal life without the side effects associated with existing drugs.

“Many medicines have unwanted side effects because they work by simply turning receptors on or off, even though we know that most of these proteins have the potential for more graded levels of response that can become highly relevant in the contexts of tissue specificity, disease and individual patient profiles,” said Professor Sexton. “We have discovered a more tailored way to exploit this functionality, by targeting regions on the receptors that act more like dimmer switches rather than on/off switches.”

Professors Christopoulos and Sexton say that almost half of all medications available target protein receptors. The groundbreaking research could lead to a new generation of drugs to precisely treat a range of diseases and conditions, including obesity, diabetes and schizophrenia.

“We have found molecules that can subtly dial up or dial down the effect of the receptor protein, or even ‘dictate’ which pathways it can or can’t signal to,” said Professor Christopoulos. “This means we could in theory treat a range of diseases with this approach more effectively and safely by avoiding some of the side effects associated with standard on/off-type drugs. Because an allosteric mechanism is more subtle and ‘tuneable’, medicines based on this principle can allow patients to lead a more normal life, especially those with chronic conditions.”

In recognition of their work, Professors Christopoulos and Sexton were congratulated on winning the GSK Award for Research Excellence at the annual Research Australia Awards. Presented on 16 November, the GSK Award for Research Excellence is one of the most prestigious available to the Australian medical research community and includes an $80,000 prize to help the winners progress their work.

Dr Andrew Weekes, medical director, GSK Australia, said GSK is proud to be able to support local researchers with the award, now in its 36th year.

“The award has been given to some remarkable people over the years, many of whom are eminent academics in their field,” said Dr Weekes. “GSK is honoured to support the research community and excited by their discoveries, which we believe will one day help patients.”

The professors say winning the GSK Award for Research Excellence is a great recognition of the efforts of all the scientists who have worked in this area over the years, often in the face of early scepticism.

“This award will greatly assist us in progressing our research on allosteric modulation into new areas and accelerate the possibility of helping patients suffering from a range of diseases that represent global health burdens but remain suboptimally treated,” said Professor Sexton.

Pictured: Professors Christopoulos and Sexton in their lab.