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Deceiving the immune system and avoid getting poisoned

​Russian scientists have developed a simple and highly efficient method of neutralization of organophosphorus compounds, the basis of the majority of chemical weapons. Nano transporter delivers the antidote directly to the point affected by the poison^ which is then chemically blocked.

Deceiving the immune system and avoid getting poisoned

The story started in 1938, when two German chemists from a large industrial concern called IG Farben tried to develop an effective pesticide, but ended up creating an organophosphorus chemical agent sarin. Terrorists still frequently use it – the tragic event that happened in Tokyo metro is one example. The scientists passed the formula to Wehrmacht, which led to the creation of three other notorious chemical G-series agents – soman, cyclosarin and tabun.

That was the birth of the first organophosphorus chemical agents. After WWII Great Britain and the USSR developed their own perfect killer agents of the same group – nerve gases VX and VR. Recently the name VX reappeared in the news feed: it was used to poison Kim Jong Nam, the brother of Kim Jong Un. However, organophosphorus compounds are also used in pesticide production – and they also present a great danger.

What is the mechanism of action of such compounds?

One has to describe how signals are transferred from neuron to neuron. Two neurons are joined together by the so-called synapse, a structure that transfers an electric or chemical signal: the transmitter neuron releases into synaptic cleft neurotransmitters (e.g. the well known dopamine and serotonin), which contact the receptors at the receiver neuron and thus the signal travels on. In motor nerves acetylcholine plays the role of the neurotransmitter. Excess of acetylcholine is hydrolyzed by an enzyme called acetylcholinesterase to prevent the nervous impulse from going on indefinitely.

Organophosphorus chemical agents affect that particular enzyme. They block the action of acetylcholinesterase, which leads to paralyses.

Scientists have long been working to develop antidotes to such chemical agents. There has been some success, but unfortunately the antidotes did not guarantee a 100% result and require a high dosage use.

Researchers from the Moscow State University led by enzyme specialist Elena Yefremenko have developed the enzyme of organophosphate hydrolase, which efficiently blocks the action of nerve agents, but which has two serious drawbacks. The first drawback is related to the fact that the hydrolase is a bacterial enzyme and is treated by the immune system as an alien substance, which causes an immune response that weakens the antidote effect. In addition, the hydrolase is quickly removed from the body. The second drawback is related to the fact that organophosphate hydrolase itself is not very stable and can decompose in only one month at zero temperature.

And at that point another invention by Alexander Kabanov, a Russian scientist, a chemist from the MSU working at the University of North Carolina and the University of Nebraska, served to solve the problem.

In 2010 Kabanov together with Prof. Natalia Klyachko of the MSU received a grant and set up a laboratory to improve the so-called nanozymes he had already developed – the nanosized polymeric micelles, the transportation vehicles for the delivery of enzymes into the brain to treat apoplexy, Parkinson disease and other diseases.

“In the 1980s our Moscow group and independently our Japanese colleagues led by Prof. Kazunori Nakaoka started using polymeric micelles to deliver small molecules as medication. Since that time the sphere of nano medicine has been going through an explosive growth stage – currently, such nanosized agents is being developed in hundreds of laboratories all over the world”, comments Alexander Kabanov.

It turns out that such nanozyme self-assembled by the effect of electrostatic interaction of the enzyme and the polymer serves as an ideal coating for organophosphate hydrolase. Nanozymes help deliver the enzymes to the point of poison action by “deceiving” the immune system. In addition, it turns out that the nanozyme coating greatly extends the shelf life of the antidote. The new “coated” enzyme has the service life of up to three years.

Tests have already proved the effectiveness of the antidote. The experiments involved mice that received a lethal dose of VX or parokson pesticide and right before or after that were given the antidote. All animals poisoned with the pesticide and 80% of animals poisoned with VX survived. Naturally, in the control group all animals died.

The original research was published in the Journal of Controlled Release under the title “Simple and highly effective catalytic nanozyme neutralizer of organophosphus nerve toxins”.

According to the scientists, the new chemical could have saved Kim Yong Nam if injected immediately after the poisoning. And, which is more important, it can save hundreds of thousands of people that annually die all over the world from pesticide poisoning: nanozymes with the enzyme are most effective is used as a preventive measure. That means they can be used as a preventive measure of chemical protection.

Alexey Payevsky

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