The European Medicines Agency approved Tecfidera in 2014 to treat of relapsing relapsing MS, a neurodegenerative condition that affects millions of people worldwide. Multiple is caused by inflammation that causes damage to the myelin-like protective layer that surrounds the nerves and the nerves themselves.
The active ingredient in Tecfidera is dimethyl fumarate. It is a compound believed to regulate the immune system, acting as an anti-inflammatory drug that helps to reduce the symptoms of MS.
But there was a detail of Tecfidera’s approval that might have been a little less well-known: it introduced to the market a part of the relatively unknown and yet largely unexplored class of drugs known as reactive electrophiles.
Reactive electrophilic chemicals such as dimethyl fumarate “seek” to bind with atoms and other molecules with an electron pair. Adding an electrophilic unit to specific drugs can significantly increase the pharmacological effectiveness and has led to an abundance of research into this area.
However, we don’t know how electrophilic reactive drugs actually function. This makes it hard to anticipate and develop new ones. The main problem is that reactive electrophiles may be very “promiscuous”, which means they may bond with a variety of targets, in addition to the ones they are designed to. This can lead to unexpected side effects and toxicities and even death.
A team of EPFL scientists led by Professor YimonAye made a major breakthrough in understanding the effects of reactive electrons on the body. The researchers employed a method called “targetable reactive electrophiles and Oxidants” or T-REX, which is short for. Professor Aye developed T-REX as well as other REX technologies during her research at Cornell University to understand the mechanisms behind electrophile signaling. The T-REX technique, which releases an electrophile to protein target and was first published in the year 2016. It is visible in time and space, as well as in live cells, the consequences of which were observed.
In this study, the researchers modified T-REX to be compatible with zebrafish (a technique they called Z-REX) and then used it to investigate the interactions of the electrophilic dimethyl fumarate in Tecfidera and how those interactions result in the immunomodulating effects of Tecfidera.
The scientists focused on Keap-1, a protein which is believed to be a metastasis and cancer suppressor. It has been discussed as a possible target of dimethyl fumarate. They used Z-REX to target Keap-1 by using electrophiles of various types. They discovered that a few of these activated a signaling pathway that results in the death of macrophages as well as neutrophils.
This pathway also includes new protein players that were never thought of in the Tecfidera field. By eliminating these “players” researchers discovered that the anti-inflammatory properties of Tecfidera which make it a treatment for multiple sclerosis, were abolished as well.
The study demonstrates that Z-REX, and by extension the REX technologies, are efficient instruments to study the interactions between electrophilic compounds and drugs in living organisms.
Poganik, J. R., et al. (2021) Wdr1 and cofilin are the key mediators of immune-cell-specific apoptosis that is triggered by Tecfidera. Nature Communications. doi.org/10.1038/s41467-021-25466-x.
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