Medical Researchers Design Variant of Main Painkiller Receptor

Opioids, such as morphine, are still the most effective class of painkillers, but they come with unwanted side effects and can also be addictive and deadly at high doses.

Designing new pain-killing drugs of this type involves testing them on their corresponding receptors, but access to meaningful quantities of these receptors that can work in experimental conditions has always been a limiting factor. Now, an interdisciplinary collaboration between researchers at the University of Pennsylvania has developed a variant of the mu opioid receptor that has several advantages when it comes to experimentation. This variant can be grown in large quantities in bacteria and is also water-soluble, enabling experiments and applications that had previously been very challenging or impossible.

The mu opioid receptor belongs to a class of cellular membrane proteins called G protein-coupled receptors, or GPCRs. Involved in wide range of biological processes, these receptors bind to molecules in the environment, initiating cellular signaling pathways. In the case of this receptor, binding to opioid molecules leads to a profound reduction of pain but also to a variety of unpleasant and potentially fatal side-effects, a problem that researchers from multiple disciplines are attempting to address.

Experimenting on the mu opioid receptor has been challenging for several reasons. The human receptor itself is relatively scarce, making harvesting appreciable amounts impractical. Researchers have also been unable to grow it recombinantly - genetically engineering bacteria to express the protein en masse - as some parts of the protein are toxic to E. coli. Hydrophobic, or water-hating, amino acid groups on the exterior of the receptor that help it sit in the cell's membrane also make it insoluble in water when isolated. The researchers set out to address these challenges by computationally designing variants of the mu opioid receptor.