Mapping TYK2 reveals new paths for immune therapy
A protein long studied in autoimmune disease turns out to offer more drug targets than previously thought. And some people are naturally protected, thanks to variants in their genes.
Tyrosine kinase 2 (TYK2) is an enzyme involved in immune signalling. First-generation TYK2 inhibitors already work in some autoimmune conditions, but not all. To understand why, a team applied a technique called deep mutational scanning: they tested more than 23,000 variations of the TYK2 protein and measured the effect on two separate functions simultaneously. The researchers describe the findings in eLife.
What does deep mutational scanning reveal?
Deep mutational scanning allows researchers to test at scale which changes in a protein’s amino acids increase, reduce or block its function. The result is a detailed map of the protein, including positions you would not immediately identify as drug targets. Using this approach, the team discovered new allosteric sites: locations on the protein that influence its activity without sitting directly in the active centre.
A notable finding: both common and rare human TYK2 variants that protect against autoimmune disease do not work by directly blocking the protein. Instead, they reduce the amount of TYK2 protein inside the cell. This suggests that degrading the protein may be a separate therapeutic strategy, alongside inhibiting its activity.
What does this mean for drug development?
The study is preliminary and based on laboratory techniques. Clinical applications do not yet exist. But the results provide leads for where next-generation TYK2 inhibitors could target the protein, and why certain human genetic variants confer protection. That kind of insight helps develop more precisely targeted drugs for conditions such as psoriasis or inflammatory bowel disease.
From a longevity perspective, the approach is relevant: a better understanding of how immune signalling works at the molecular level allows more precise intervention in the inflammatory processes that contribute to ageing.