A joint effort between researchers at Merck Research Laboratories (named MSD outside the U.S. and Canada), Eindhoven University of Technology (TU/e) and Leiden University, both in The Netherlands, has led to the discovery of a completely new way to block a human nuclear receptor, with possible implications for Crohn’s disease. The study, entitled “Identification of an allosteric binding site for RORγt inhibition” – published in the journal Nature Communications on December 7 – is a breakthrough in drug development research.

Nuclear receptors are crucial for a large number of physiological processes, and they are also involved in numerous pathological states. They are, therefore, attractive targets for drug development. Drugs targeting nuclear receptors constitute 13 percent of the medications available on the market today.

Currently available drugs all use the same mechanism when interacting with the receptor ­– targeting the receptor’s natural ligand binding site. However, this approach is surrounded by a number of serious disadvantages, such as selectivity problems. Also, developing resistance may render drugs useless, and searching for substances targeting orphan receptors – where the identity of the natural ligand isn’t known – is a difficult task when tailoring substances to fit a receptor’s main binding site.

Researchers, while studying a nuclear receptor called RORγt, discovered that the receptor had another binding site. When a specific class of substances was applied to the receptor, this binding site became blocked, inducing an unprecedented conformational change on the receptor structure, which blocked interactions with the natural ligand.

In a press release from Eindhoven University, the team refers to the finding as “the back door of the nuclear receptor,” stating that this mechanism is less likely to lead to compensatory changes in receptor signaling, hence preventing drug resistance and decreased efficiency issues.

The RORγt is a nuclear receptor required for the function of T17 cells, immune cells that mediate inflammation and cytokine release, being involved in several autoimmune disorders, including intestinal inflammation and Cronh’s disease. The results, however, may have implications far beyond autoimmune diseases. TU/e Professor of Chemical Biology and study’s senior author, Dr. Luc Brunsveld noted, “For the first time in fifty years, research has identified an effective means for drugs to bind to a novel site on a nuclear receptor and thus inhibit it.”

Humans have 48 known nuclear receptors, and the finding inspires hope that some of the other 47 receptors might have similar binding sites, opening up the possibility to develop a new class of drugs that are superior to current medications. “I anticipate a flow of further research geared to investigating the potential of this concept,” concluded Dr. Brunsveld, who expects the finding to have an imminent impact on the drug development field.