A study by scientists at the Scripps Research Institute has helped to demystify the molecular workings of the multiple sclerosis (MS) drug Tecfidera (dimethyl fumarate [DMF], Biogen). The drug is the most widely prescribed pill-based therapy for MS, but its biological mechanism of action has been a mystery.
Using a new technology that can reveal a drug’s protein targets, the scientists showed that Tecfidera interacts with multiple T-cell proteins, in some cases inhibiting their activity, and helping to suppress the T-cell activation that is a key feature of MS flare-ups.
The study was reported in Science Signaling.
Despite its relatively recent (2013) FDA approval for the treatment of MS patients, Tecfidera is neither new nor high-tech, the researchers said. It is a relatively simple organic compound, DMF, that has been in the biomedical literature for decades. DMF was once used in Europe to prevent mold growth in sofas during storage and shipping, although the European Union banned it from consumer products in 2009 after it was linked to severe allergic skin reactions. It has proved more useful as a pharmaceutical. Since the 1990s, it has been an effective treatment for psoriasis, an autoimmune skin disease. Success against psoriasis led to its investigation as a potential MS drug.
Until recently, the leading theory was that DMF works against MS primarily by unleashing the activity of a protein called Nrf2, which helps protect the brain from autoimmune damage by marshaling a powerful antioxidant response and which may also reduce immune-system activation. Studies published during the past year have suggested, however, that DMF works principally by reducing immune-system activity and does so independently of Nrf2.
The TSRI team found that within activated human T cells, DMF reacts with approximately 50 different cysteines, in about as many proteins. The affected proteins include enzymes and regulators of gene activity.
The researchers confirmed that DMF blocks the activation of T cells, and that it does so, at least in part, by targeting two cysteine residues on the immune-cell signaling enzyme PKCθ, thereby preventing PKCθ from associating with CD28, another protein needed for T-cell activation.
Even in T cells lacking PKCθ, DMF was able to reduce signs of activation further. That and other evidence strongly suggested that the full immune-damping effect of DMF results from its interactions with multiple proteins.
The researchers are now developing other compounds that might modulate immune activity in a more-precise manner—hitting only the most important cysteine targets, for example on PKCθ—with fewer adverse effects.
“We’re interested ultimately in making more selective, site-specific drugs, both to reduce immune activity and to boost it,” said co-author Dr. John R. Teijaro.