A team led by Professor WANG Peng at the Hefei Institutes of Physical Science of the Chinese Academy of Sciences has developed and structurally resolved a new long-acting insulin analog called insulin lisargine, which offers enhanced purity, strong glucose-lowering performance, and a favorable safety profile.
The findings were recently published in Scientific Reports.
Insulin analogs are essential for diabetes treatment, but their production can be complicated by impurities and structural instability. For example, insulin glargine, one of the most widely used long-acting insulins, can form unwanted by-products during manufacturing. This challenge has driven efforts to design next-generation analogs that are more stable, easier to produce, and offer improved therapeutic performance.
In this study, the team applied precise molecular engineering: Asn at position A21 was replaced with Gly, and Lys and Arg were introduced at positions B31 and B32. This design prevents impurity formation seen in glargine production and significantly improves purity. The researchers also established a scalable manufacturing workflow to produce high-purity insulin lisargine.
Using X-ray crystallography at 2.0 Å resolution, the team resolved the 3D structure of insulin lisargine. High-resolution mass spectrometry confirmed that its molecular weight matches the theoretical value, validating structural accuracy and purity.
In biological studies, insulin lisargine demonstrated superior glucose-lowering efficacy in type 1 diabetic rat models, particularly at 5 IU/kg, where it outperformed glargine. Long-term toxicokinetic tests in beagle dogs revealed no evident toxicity, supporting its potential for industrial and clinical use.
“This work systematically clarifies the molecular structure and mechanism of action of insulin lisargine and demonstrates its potent glycemic control with favorable safety,” said Prof. WANG. “It offers a promising new candidate for diabetes therapy.”
Crystal structure and X-ray diffraction analysis of the insulin analog (Image by SUN Manman)