“Nature may have come up with a beautiful design in the insulin molecule, but that doesn’t mean it can’t be improved,” says Associate Professor Andrea Robinson from Monash University’s School of Chemistry.
Regular doses of insulin are essential to the health of almost 300 million people around the world who have diabetes. Their bodies produce little or no insulin, which is needed to turn glucose from food into energy.
But insulin in its natural form, or in the available synthetic forms, must be kept at four degrees Celsius or it loses its potency. “If you can’t keep milk, you can’t keep insulin,” Associate Professor Robinson says. That creates a logistical problem when it comes to distributing insulin to areas such as remote Australia and much of the developing world.
At higher temperatures, the insulin molecule’s shape changes and it can no longer interact with receptors on cells to regulate glucose metabolism.
A key to understanding this instability can be found in insulin’s disulfide framework. If any one of these sulfur bridges breaks, the insulin molecule unravels into a form that not only exposes it to the risk of breaking down, but also means it can no longer interact with its receptor in the body and activate the required insulin response. The same goes for synthetic insulin, the life-saving replacement for people whose bodies do not produce any or enough insulin.
These sulfur atom bridges provide Associate Professor Robinson with an ideal target in her quest to strengthen the insulin molecule. Developments in the work on this unstable molecule mean that there could soon be a form of synthetic insulin that can resist higher temperatures, a factor that could simplify the storage of therapeutic insulin.
“Over the past five years we have developed a generic toolbox of chemical reactions that enables us to take peptide [small protein molecule] structures of nature’s design and to replace parts of those molecules that are unstable and are going to be degraded very quickly,” Associate Professor Robinson says.
To strengthen the insulin molecule, the researchers are replacing the sulfur atoms with carbon. “We use chemistry to replace the sulfur across the bridges and we put in carbon instead. This makes the bonds very stable and they can’t degrade via the regular way that nature would normally use,” says Associate Professor Robinson, who is collaborating with the University of Adelaide’s Dr Briony Forbes and Associate Professor Sof Andrikopoulos from the University of Melbourne. The resulting insulin with its ‘dicarba’ bridges is far more stable than existing forms.
“These insulins have amazing physical stability, because we can heat them to 90 degrees Celsius and they retain their structure,” Associate Professor Robinson says.
There is also another potential benefit for patients. To do its work, insulin binds to a variety of receptor molecules located on the surface of cells, like TV antennas channelling reception. Current synthetic insulins activate a broad family of receptors, including the ‘insulin-like growth factor’ receptor that is associated with cellular proliferation and therefore, potentially, cancer. The altered insulin more exclusively targets only the insulin receptor.
Associate Professor Robinson’s work with dicarba bridges also has applications in improving the stability and potency of another potential therapeutic with disulfide bridges: conotoxins derived from marine cone snails. This work, a collaboration with Professor Ray Norton from Monash and RMIT University’s Professor David Adams, could lead to the development of treatments for many medical conditions with overactive pain neurons.
“Conotoxins are very potent analgesics and they’re not addictive like morphine,” says Associate Professor Robinson. “So they have great potential for the treatment of chronic pain.”
