posted on 2021-03-08, 18:05authored byFemke
A. Meijer, Maxime C. M. van den Oetelaar, Richard G. Doveston, Ella N. R. Sampers, Luc Brunsveld
The nuclear receptor
RORγt is a key positive regulator in
the differentiation and proliferation of T helper 17 (Th17) cells
and the production of proinflammatory cytokines like IL-17a. Dysregulation
of this pathway can result in the development of various autoimmune
diseases, and inhibition of RORγt with small molecules thus
holds great potential as a therapeutic strategy. RORγt has a
unique allosteric ligand binding site in the ligand binding domain,
which is distinct from the canonical, orthosteric binding site. Allosteric
modulation of RORγt shows high potential, but the targeted discovery
of novel allosteric ligands is highly challenging via currently available
methods. Here, we introduce covalent, orthosteric chemical probes
for RORγt that occlude the binding of canonical, orthosteric
ligands but still allow allosteric ligand binding. Ultimately, these
probes could be used to underpin screening approaches for the unambiguous
and rapid identification of novel allosteric RORγt ligands.