Researchers of the Monash Institute of Pharmaceutical Sciences (Melbourne, Australia) have made an important breakthrough in understanding how a major diabetes and obesity drug target, the glucagon-like peptide-1 receptor (GLP-1R) can be differentially activated by natural and potential therapeutic molecules.
 
Diabetes is a wide-spread chronic illness that can lead to major organ failure and death, and globally affects nearly 10% of the population (http://www.who.int/mediacentre/factsheets/fs312/en/), with incidence of the disease rising in parallel with the large increase in obesity.
 
Drugs such as Byetta® and Victoza® that act via the GLP-1R are now prescribed to over one million people in the United States, with over $2 billion in sales. These drugs act by mimicking the natural hormone for this receptor, GLP-1.
 
“What we are learning is that these drugs can have distinct actions via the GLP-1R and that these differences, termed ‘biased agonism’, can lead to differential therapeutic effects, but this had not been considered during early drug development”, noted Professor Patrick Sexton, Scientific Advisor to the Chinese National Center for Drug Screening and International Adjunct Professor at School of Pharmacy, Fudan University (both located in Shanghai) and a co-corresponding author for the paper.
 
One of the most interesting recent discoveries is that a ‘biased’ GLP-1R agonist, exendin-P5 (an analogue of Byetta®), possesses potent anti-diabetic effects in experimental disease models, but with a distinct mode of action from approved GLP-1R mimetics that could enhance clinical outcomes if they translated into patients.
 
In a paper published online on February 21, 2018 in the journal Nature entitled “Phase-plate cryo-EM structure of a biased agonist-bound human GLP-1 receptor–Gs complex”, Monash Researchers, working collaboratively with scientists in Germany, China and the United States, have provided molecular details of why exendin-P5 acts differently from other GLP-1R ligands.
 
“We have taken advantage of last year’s Nobel Prize winning advances in cryo-electron microscopy to achieve this breakthrough in structural biology, and in doing so have demonstrated that we are capable of achieving a resolution that can guide rational drug design for the largest class of drug targets ‒ G protein-couple receptors”, said Dr. Lynn Liang, a lead author of the paper.
 
Dr. Denise Wootten, who directed the project, commented “We have been able to identify specific areas of the target that interact differently to drive the functional difference. This knowledge can guide how to develop new drugs to capture beneficial features in signalling that may better treat diseases”.
 
Drugs that target GLP-1R have also been approved for obesity and are in clinical trials for treating neurodegenerative disorders, including Alzheimer’s and Parkinson’s disease. “Tailoring the signalling of drugs for optimum treatment of individual disease should lead to improved clinical outcomes, and the work is a significant step towards this goal”, said Professor Ming-Wei Wang, Director of the National Center for Drug Screening, Dean of Fudan School of Pharmacy, an expert in GLP-1R pharmacology and a senior author of the paper, who and his Ph.D. student, Ms. Saifei Lei, from Shanghai Institute of Materia Medica, Chinese Academy of Sciences, participated in the collaboration.

 
Cryo-EM structure of a biased agonist (exendin-P5) bound glucagon-like peptide-1 receptor–Gs complex

Link:http://rdcu.be/HxCo