Glucose-grabbing macrocycle helps insulin adjust to blood sugar

By tethering insulin to a glucose-grabbing macrocycle and a glucose mimic, scientists have created a switchable form of the diabetes treatment that responds to blood sugar levels. The engineered insulin could protect against hypoglycemia—a potentially life-threatening condition that people with diabetes can experience when their blood sugar levels become too low.

A team led by Novo Nordisk’s Rita Slaaby developed the glucose-responsive insulin, which is called NNC2215. The insulin in NNC2215 makes links to two moieties: a glucose-binding macrocycle and a glucoside, which mimics glucose.

When there’s little or no glucose present, the glucoside forms a supramolecular complex with the macrocycle. This complex blocks the engineered insulin from binding to its receptor. But when blood sugar levels rise, NNC2215’s macrocycle releases the glucoside and binds to glucose. This action opens the switch so that the engineered insulin can bind to its receptor and start the process of bringing sugar into cells (Nature 2024, DOI: 10.1038/s41586-024-08042-3).

The switching mechanism works at glucose concentrations that are physiologically relevant. This makes the work “a benchmark in the field of macromolecular medicinal chemistry,” says Richard DiMarchi, a chemistry professor at Indiana University Bloomington who has worked on insulin for decades, including time at Novo Nordisk and Eli Lilly and Company, but was not involved with the development of NNC2215. When the glucose concentration increases from 3 to 20 mM, the insulin receptor’s affinity for NNC2215 increases more than threefold. It’s a tight range, DiMarchi says.

“This is not a light switch. This is a dimmer, meaning it’s not on or off,” DiMarchi says. NNC2215’s activity rises and falls with glucose levels.

Slaaby’s team showed that NNC2215 can lower blood sugar levels in rats and pigs with diabetes without causing hypoglycemia. But DiMarchi says the scientists still need to demonstrate that NNC2215 can work as a chronic therapy. He also points out that engineered insulin may cause an immune response and that NNC2215’s complex synthesis might be expensive.

Chemists in Anthony P. Davis’s lab at the University of Bristol reported the first version of NNC2215’s macrocycle in 2018. Davis, a coauthor on the Nature paper, says the macrocycle was the culmination of about 3 decades of work designing an exquisitely sensitive glucose binder.

Andy Chapman, CEO of the molecular recognition company Carbometrics and another coauthor on the paper, says that although the researchers had to address many challenges to create a practical glucose-binding system—including selectivity, stability, and mechanism—synthesizing the macrocycle was always in the back of his mind. “I always used to think, Even if we solved all of those challenges, how are we going to make it? How are we going to make enough?”

Chapman says the first synthesis was “an utter nightmare” in which the chemists would fish out the macrocycle from a complex reaction mixture using high-performance liquid chromatography. Carbometrics chemists worked with chemists at Novo Nordisk and the contract research organization Apigenex to improve the macrocycle’s synthesis so that it could be made in 95% purity without the need for chromatography. “It is staggeringly optimized now,” Chapman says.

Slaaby and Novo Nordisk declined C&EN’s request for an interview. When a spokesperson was asked if the company was planning to move the glucose-sensitive insulin into human studies, they replied that further research to optimize NNC2215’s pharmacological properties is ongoing.