New drug against nerve agents in sight

New drug against nerve agents in sight

10:09 AM, 3rd May 2016
New drug against nerve agents in sight
A model of how sarin and HI-6 are positioned in the protein acetylcholinesterase just before HI-6 removes sarin and restores the function of the protein. Sarin in magenta, HI6 in green, oxygen in red, phosphorus in orange and nitrogen in blue.

UMEA, SWEDEN: Umea University researchers said that the nerve agent sarin causes a deadly overstimulation of the nervous system that can be stopped if treated with an antidote within minutes of poisoning.

The study is collaboration between Umea University, the Swedish Defence Research Agency and the German Bundeswehr Institute of Pharmacology and Toxicology.

The results were published in the journal Proceedings of the National Academy of Sciences (PNAS).

Sarin is a colourless, odourless liquid fatal even at very low concentrations. Serious sarin poisoning causes visual disturbance, vomiting, breathing difficulties and finally, death.

“Nerve agents are dreadful weapons, and our hope is for these results to lead to improved drugs against them,” said Anders Allgardsson, Biochemist at the Swedish Defence Research Agency (FOI).

Nerve agents destroy the function of a very important protein in the nervous system called acetylcholinesterase (a chemical compound). As long as the nerve agent is bound to the protein, the breakdown of an important signal substance is prevented. The antidote HI-6 removes the nerve agent and restores the function of the nervous system. Drugs against nerve agent poisoning have been used for a long time, still it has been unclear how they actually work.

After years of hard work, chemists from FOI and Umea University are now presenting a three-dimensional structure that depicts the HI-6 moments before the bond between the nerve agent and the protein is broken. The structure gives a high-resolution image that, in detail, describes the individual positions of atoms and provides an understanding of how the bond breaks.

The scientific breakthrough was enabled by combining three-dimensional structural depictions with advanced calculations and biochemical experiments.

“With the help of X-ray crystallography, we could see weak traces of the signal we were looking for. As the signal was weak, we decided to integrate the data with quantum chemical methods. After demanding calculations on the supercomputer at the High Performance Computing Center North (HPC2N) at Umea University, we finally succeeded,” said Anna Linusson, professor at the Department of Chemistry at Umea University.

The calculations supported the theory that the weak signal in the X-ray crystallography data actually came from HI-6 and sarin. Important knowledge also fell into place after experiments where the system was disturbed by mutating the protein or by introducing isotopes.

“After seven years of work using many different techniques, we have finally been able to bring this to a successful close and can show a uniform picture of how HI-6 approaches sarin. It opens up for new opportunities in finding antidotes to sarin and other nerve agents by structure-based molecular design,” said Anders Allgardsson.

© Umea University News



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