A team led by Rita Slaby at Novo Nordisk has developed a glucose-responsive insulin called NNC2215. Insulin in NNC2215 binds to two moieties: a glucose-binding macrocycle and a glucoside that mimics glucose.
When little or no glucose is present, glucosides form supramolecular complexes with macrocycles. This complex blocks artificial insulin from binding to its receptor. However, when blood sugar levels rise, the macrocycle of NNC2215 releases glucosides that bind to glucose. This action opens a switch that allows the engineered insulin to bind to its receptor and begin the process of bringing sugar into the cell (nature 2024, DOI: 10.1038/s41586-024-08042-3).
This switching mechanism operates at physiologically relevant glucose concentrations. This makes the study “a benchmark in the field of polymer medicinal chemistry,” he said. Richard DiMarchiA chemistry professor at Indiana University Bloomington, he has worked on insulin research for decades, including stints at Novo Nordisk and Eli Lilly and Company, but was not involved in the development of NNC2215. As the glucose concentration increases from 3 to 20 mM, the affinity of the insulin receptor for NNC2215 increases by more than 3-fold. DiMarchi says that's a narrow scope.
“This is not a light switch. It's a dimmer, meaning it's neither on nor off,” DiMarchi said. The activity of NNC2215 increases or decreases depending on glucose levels.
Slaaby's team showed that NNC2215 can lower blood sugar levels in diabetic rats and pigs without causing hypoglycemia. But DiMarchi said scientists need to prove that NNC2215 works as a chronic therapy. He also points out that artificial insulin can trigger an immune response, and that NNC2215's complex synthesis can be expensive.
chemist Anthony P. DavisA lab at the University of Bristol reported the first version of the NNC2215 macrocycle in 2018. nature The paper says the macrocycle is the culmination of nearly 30 years of research to design extremely sensitive glucose binders.
Andy Chapman, CEO, Molecular Recognition Company carbometrics Another co-author of the paper said researchers had to address many challenges to create a practical glucose-binding system, including selectivity, stability, and mechanism, but macrocyclic He says that the synthesis of molecules was always in the back of his mind. “I always thought, 'Even if I solve all these challenges, how am I going to be successful? How am I going to make enough money?'”
Chapman says the initial synthesis was “an absolute nightmare,” with chemists using high-performance liquid chromatography to find the macrocycle from a complex reaction mixture. Carbometrics chemists collaborated with chemists from Novo Nordisk and contract research organizations Apigenex We have improved the synthesis of macrocycles so that they can be produced in 95% purity without the need for chromatography. “It's incredibly optimized now,” Chapman says.
Slarby and Novo Nordisk declined C&EN's requests for an interview. When asked if the company plans to move its glucose-sensitive insulin into human studies, a spokesperson said further research is underway to optimize NNC2215's pharmacological properties.