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Scientists discover 'back door' of nuclear receptor

Discovery opens the way to drugs that are not susceptible to resistance, for all kinds of diseases

Eindhoven University of Technology

On Monday 7 December the journal Nature Communications published the research findings of Eindhoven University of Technology (TU/e), Merck Research Laboratories (Merck is known as MSD outside the US and Canada) and Leiden University concerning an entirely new way of antagonizing a human nuclear receptor. The Eindhoven researchers expect the discovery to have significant impact in the world of drug research. Nuclear receptors are modulatory proteins that control numerous crucial bodily functions and thus also play a key role in many pathologies. A new, potentially better method has been found to impact the function of these proteins. This opens an avenue whereby drugs could be developed with a decreased susceptibility to resistance, for the treatment of myriad diseases.

The human body contains approximately 48 genes encoding nuclear receptors. Given their crucial role in pathologies, these proteins are preferred targets for drug discovery and development. Nuclear receptors are the target for approximately 13 percent of all available pharmaceuticals - from prostate cancer treatments to oral contraceptives. These drugs all work using the same mechanism: they bind to a receptor at the same site as its natural ligand and thereby influence its behavior.

The published research focuses specifically on the RORγt receptor, which plays an important role in auto-immune diseases like rheumatism and Crohn's disease. The researchers have discovered that a particular class of molecules binds to a previously unknown site on RORγt and potently antagonizes this nuclear receptor's function. The main advantage of this new mode of action is that it uses a kind of back door of the nuclear receptor that endogenous ligands do not access. This suggests that any compensatory mechanism the human body may make in ligand production would be less likely to induce resistance and decrease efficacy.

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, explains Luc Brunsveld, TU/e professor of Chemical Biology. This opens the way for new drugs for auto-immune diseases. But the impact could go beyond this. Perhaps some of the other 47 known receptors can be blocked in the same way. This could enable a new class of drugs that function differently, and potentially better, than current medications. "This news is going to have a major effect on the field of drug development," Brunsveld expects. "I anticipate a flow of further research geared to investigating the potential of this concept."


Identification of an Allosteric Binding Site for RORyt Inhibition. Nature Communications, published online on 7 December 2015. doi: 10.1038/ncomms9833

Marcel Scheepstra (1), Seppe Leysen (1), Geert C. van Almen (1), J. Richard Miller (2), Jennifer Piesvaux (2), Victoria Kutilek (2), Hans van Eenennaam (2), Hongjun Zhang (2), Kenneth Barr (2), Sunil Nagpal (2), Stephen M. Soisson (2), Maria Kornienko (2), Kristen Wiley (2), Nathaniel Elsen (2), Sujata Sharma (2), Craig C. Correll (2), B. Wesley Trotter (2), Mario van der Stelt (2, 3), Arthur Oubrie (2), Christian Ottmann (1), Gopal Parthasarathy (2), Luc Brunsveld (1).

(1) Eindhoven University of Technology
(2) Merck Research Laboratories
(3) Leiden University

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