Sweet substitution: NMR and insulin analogue

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  • Published: Jan 6, 2017
  • Author: David Bradley
  • Channels: NMR Knowledge Base
thumbnail image: Sweet substitution: NMR and insulin analogue

Hormone substitution

Binding of the insulin analog (green) to the receptor (light blue). The receptor’s surface is shown in transparent gray. © University of Basel, Department of Chemistry

Replacing a particular hydrogen with an iodine atom to create a halogenated insulin analogue maintains the functionality of the glucose-control hormone but makes it act much faster. Nuclear magnetic resonance spectroscopy and X-ray crystallography have been used to investigate the structure.

Insulin is made by the pancreas and regulates the concentration of glucose in blood plasma, disruption of the system are the underlying problem in diabetes. The hormone is stored in the body as a zinc-bound complex of six identical molecules protein monomers in a hexameric system. However, the physiologically active form is the single insulin monomer, which must be liberated from the hexamer when it is needed to carry out blood sugar regulation. Researchers at the University of Basel, Switzerland, were well aware of research into halogen-substituted proteins and have now predicted the effect of an iodine substitution on the way in which hexameric insulin breaks up into six monomers using computer simulations. The findings were then confirmed with laboratory experiments and the details published in the Journal of Biological Chemistry.

Artificial insulin compounds have been sought for many years as an alternative to the natural substance with the aim of shortening response times on injection by patients with diabetes and even to develop orally active analogues that would work when taken by mouth rather than injected. Speeding up the hexamer disassembly process in an artificial insulin preparation is a primary target of research so that clinical treatment of diabetes mellitus might be optimised. By means of chemical modifications, the release and availability of insulin can be improved.

Vital protein

Basel chemist Markus Meuwly and Krystel El Hage collaborated with Vijay Pandyarajan, Nelson Phillips, Jonathan Whittaker, and Michael Weiss of Case Western Reserve University, and Brian Smith of La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Australia, and John Menting of The Walter and Eliza Hall Institute of Medical Research, in Parkville, both in Victoria, Australia in the hope of finding more effective, faster-acting insulin analogues through simple chemical changes to the structure of this vital protein. Perhaps the simplest change they could make was to replace a hydrogen atom in a conserved tyrosine (TyrB26) amino acid in insulin. The team's computer calculations on this analogue suggest that there are subtle differences between the interactions of the aromatic rings between pairs of monomers. Given that the disassembly of the hexamer hinges on this amino acid to some extent the change in interaction should give rise to a more rapid insulin disassembly and release, the team reasoned.

Fast-track insulin

Indeed, introduction of this iodine atom improved the availability of insulin but importantly did not affect the affinity of the hormone for its receptor nor disturb its biological activity otherwise in comparison with the natural hormone. Efforts in recent years with modelling of halogenated proteins meant that the team could be confident of the validity of their quantum chemistry and molecular dynamics simulations. NMR spectroscopy and crystallography confirmed the structure revealed by the computational work.

The use of halogen atoms has been used widely in small molecule compound optimization in medicinal chemistry for many years. The new results obtained for iodinated insulin demonstrate that the concept of such chemical modifications might also work with proteins potentially opening up the concepts of medicinal chemistry to these biological macromolecules. In this particular instance, the activity and properties of the iodinated insulin hold great promise for clinical testing given that insulin is the archetypal protein associated with human health and metabolic disease.

Related Links

J Biol Chem 2017, online: "Extending Halogen-Based Medicinal Chemistry to Proteins: Iodo-Insulin as a Case Study"

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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