Researchers from the Swedish Defense Research Agency (FOI) and Umeå University wanted to improve the treatment of nerve agent poisoning. In the end, they solved a 50-year-old mystery that has potential consequences for treating neurological conditions and blood pressure disorders.
Our work solves a riddle that has eluded researchers for over 50 years, says Daniel Wiktelius, chemist at the Swedish Defense Research Agency, FOI, and one of the main authors of the article published in the prestigious journal Angewandte Chemie International Edition.
The article focuses on substances that lower the activity of a critical part of the cholinergic nervous system. The cholinergic system is vital in all humans and animals. Disorders in the system occur in those who are poisoned by nerve agents but are also linked to diseases such as Alzheimer's and schizophrenia.
In layman terms, the function of the cholinergic system is to transport signals between the brain and various parts of the body, such as muscles. In order for the muscles to be able to relax, the signal must be terminated. Nerve agents destroy this vital function.
Traditionally used drugs for nerve agent poisoning work by either restoring the nervous system's ability to terminate the signaling or by mitigating the consequences of the excessive signaling. Researchers have now instead focused on substances and mechanisms that restrict signaling at the source, the enzyme choline acetyltransferase, abbreviated ChAT.
Through their work, they hope to develop drugs that can temporarily block ChAT and thereby reduce nerve signaling in patients poisoned by nerve agents.
In the article, the research team describes how ChAT manufactures its own inhibitor from the body's own substance coenzyme A and a group of chemicals called arylvinylpyridines.
Already in the 60's it was discovered that arylvinylpyridinines affect ChAT, but since we did not understand the mechanism, we have not succeeded in further developing these into drugs, says Anders Allgardsson, researcher at FOI. -- In the long run, our discovery may yield new drugs. For those who have been poisoned by nerve agents, it can be the difference between life and death.
Norman Hoster, doctoral student at the Industrial Doctoral School at Umeå University, comments on the importance of collaboration. -- I believe that the collaboration between Umeå University and FOI is the key to our success in resolving this complex issue. The article is a shining example of when one and one becomes three.
The mechanism discovered is very unusual, perhaps it is the first time it has been described in the research literature.
Arylvinylpyridinines and ChAT have fascinated skilled researchers for decades, but it is only now that we can explain how they actually work, says Fredrik Ekström, research director at FOI and team leader of the published study. He describes how the discovery has laid the foundation for the development of new tools for studying the nervous system.
We have shown that the inhibitor is formed by a reaction between the body's own coenzyme A and an arylvinylpyridine, and that this reaction takes place inside ChAT.
We hope to take our research beyond arylvinylpyridines and study other types of inhibitors. It would be great if our work contributes to new drugs that can cure or alleviate diseases of the nervous system, Ekström concludes.
Wiktelius, D., et al. (2020) In situ assembly of choline acetyltransferase ligands by a hydrothiolation reaction reveals key determinants for inhibitor design. Wiley. doi.org/10.1002/anie.202011989.