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Research from the National Magnetic Resonance Facility at Madison (NMRFAM) in the Department of Biochemistry examines the structural differences in crystals of various therapeutic insulin complexes. Here’s the run down on their latest research, published in the journal ChemMedChem:
- Some drugs, including insulin used to treat diabetes, are manufactured as a complex linking the drug to a protein.
- Pharmaceutical companies use different proteins in their drug formulations. Differences in the structures of these insulin-protein complexes, which could impact drug shelf-life and efficiency, have not been widely studied.
- Nuclear magnetic resonance (NMR) can be used study drug-protein complexes, which can be used in drug development and quality control.
What background information do you need to know?
Insulin is a hormone produced by the pancreas that is essential for regulating blood sugar in humans and other animals. Natural and synthetic forms of insulin have long been used to treat diabetes, a condition resulting from the body either producing too little insulin (type 1 diabetes) or having a lowered sensitivity to insulin (type 2 diabetes).
Therapeutic insulin can be administered in different forms, including as a complex where the insulin is bound to a protein. A patient who takes this type of insulin doesn’t have to time their dose of insulin with a meal, and the insulin metabolizes in their body over a longer period of time.
Linking a drug to a protein to slow its release is a well-known method in the pharmaceutical industry and is not unique to insulin. Pharmaceutical companies that produce drugs with the same or similar functions may link active compounds to different proteins to produce their own formulations. While the effectiveness of drug-protein complexes is carefully tested and drugs undergo rigorous quality control, structural comparisons have not been performed, and function implications of structural differences have not been widely studied.
Why does the drug-protein structure matter?
Structural properties of drug-protein complexes and the proteins themselves can impact a drug’s efficacy, efficiency, shelf life, and production cost. Additionally, understanding how key protein regions are similar and different may inform the development of new drugs or new formulations of existing drugs.
Solid-state nuclear magnetic resonance (ssNMR) is one of several techniques available to researchers interested in studying the crystalline structures formed by a protein linked to insulin or other drugs. ssNMR allows researchers to analyze solid compounds without needing to dissolve the samples in solution, approximating in vivo conditions. Unlike other available tools such as x-ray crystallography, ssNMR reveals information about interactions among molecules and can be used to determine structures of non-crystalline structures or imperfect crystals (as is the case for insulin-protein complexes).
How have scientists made progress?
Researchers in NMRFAM used ssNMR to determine structures of human insulin and insulin-protein crystals from two drug manufacturers. Their study was performed in collaboration with scientists at the Food and Drug Administration.
The two manufacturers used different but similar formulations for their drugs (the drugs have been found to be equally effective at treating diabetes). The researchers confirmed that there were minimal structural differences between the insulin-protein crystals produced by the manufacturers.
The researchers say that ssNMR can be applied to study the structures of other drugs and could be incorporated into drug development and quality control. For example, providing a structural baseline for different drug formulations could be used to determine the consistency among production lines or batches. Companies interested in developing generic forms of a drug could also use ssNMR as part of their suite of tests assessing biochemical similarities with compounds used in approved brand-name options.
Written by Renata Solan.
In Research In Brief: The What, Why, and How, we explore new research from the UW–Madison Department of Biochemistry to learn more about the world around us — and inside us.
This edition of Research in Brief: The What, Why, and How is based on the following publication:
is based on the following publication: Wang, Rienstra, and Chen. Higher order structure differences among insulin crystalline drugs revealed by 2D heteronuclear NMR. ChemMedChem, Dec 2024, 19(23):e202400340. This research made use of the National Magnetic Resonance Facility at Madison (NMRFAM), supported by NIH grant R24GM141526.