A tool to interrogate a new class of drugs
Reactive electrophilic drugs like Tecfidera, approved for the treatment of relapsing multiple sclerosis, show a lot of potential but are also mystery. Their effects are notoriously difficult to study, which hampers progress testing and approving them. EPFL scientists have now used an innovative chemical method to uncover the biological mechanisms of Tecfidera, providing a powerful tool for exploring other reactive electrophilic drugs.
In 2014, the European Medicines Agency approved the drug Tecfidera for the treatment of relapsing multiple sclerosis, a neurodegenerative disease that affects millions of people worldwide. In multiple sclerosis, inflammation damages the protective myelin insulation around nerves, and the nerves themselves. The active ingredient of Tecfidera is dimethyl fumarate, a compound that is thought to modulate the immune system, thus acting as an anti-inflammatory that alleviates the symptoms of multiple sclerosis.
But there was a detail of Tecfidera’s approval that might have been a little less appreciated: it brought into the market a member of the relatively new – and still largely unexplored – class of drugs known as reactive electrophiles.
Reactive electrophilic compounds like dimethyl fumarate are molecules that “seek” to bond with atoms or other molecules that have an available electron pair. Adding an electrophilic unit to certain drugs significantly increases pharmacological efficacy, which has generated a lot of research activity into this area.
The problem, however, is that we don’t know exactly how most reactive electrophilic drugs work, which makes it difficult to predict their effects and outcomes, and efficiently design new ones. The main obstacle is that reactive electrophiles seem to be very “promiscuous” inside the body or even a cell, bonding with multiple targets aside from the ones intended, which can result in unexpected side-effects and drug toxicity, and, in extreme cases, death.
Now, a team of scientists at EPFL led by Professor Yimon Aye, have been able to make a significant breakthrough in studying the effects of reactive electrophiles in the body. The scientists used a technique called “targetable reactive electrophiles and oxidants” or T-REX for short. T-REX and the broader “REX technologies” were developed by Prof. Aye during her work at Cornell University as she sought to understand the mechanisms of electrophile signaling. First published in 2016, the T-REX method releases a specific electrophile to a target protein, the ramifications of which can be observed in space and time, and in live cells.
In this study, the researchers adapted T-REX to be compatible with zebrafish (a technique they named Z-REX), and used it to systematically investigate the interactions of the electrophilic dimethyl fumarate in Tecfidera, and how those interactions produce the immunomodulating effects of Tecfidera.
The scientists targeted the protein Keap-1, a known cancer and metastasis suppressor, which has been debated as a potential target for dimethyl fumarate. Using Z-REX to target Keap-1 with various electrophiles, they discovered that some of them triggered a signaling pathway that leads results to the apoptosis of neutrophils and macrophages.
That pathway also involves some novel “protein players” that had not been considered before in the Tecfidera field. By removing these “players”, the researchers found that the anti-inflammatory effects of Tecfidera, which are what make it a treatment for multiple sclerosis, were abolished as well.
The work demonstrates that Z-REX, and by extension, the REX technologies, are effective tools for investigating the interactions of electrophilic compounds and drugs in living organisms.
NCCR Chemical Biology
Jesse R. Poganik, Kuan-Ting Huang, Saba Parvez, Yi Zhao, Sruthi Raja, Marcus J. C. Long, Yimon Aye. Wdr1 and Cofilin are Necessary Mediators of Immune-Cell-Specific Apoptosis Triggered by Tecfidera. Nature Communications 30 September 2021. DOI: 10.1038/s41467-021-25466-x