Orthosteric and Allosteric Dual Targeting of the Nuclear Receptor RORγt with a Bitopic Ligand.

ABSTRACT: The RORγt nuclear receptor (NR) is of critical importance for the differentiation and proliferation of T helper 17 (Th17) cells and their production of the pro-inflammatory cytokine IL-17a. Dysregulation of RORγt has been linked to various autoimmune diseases, and small molecule inhibition of RORγt is therefore an attractive strategy to treat these diseases. RORγt is a unique NR in that it contains both a canonical, orthosteric and a second, allosteric ligand binding site in its ligand binding domain (LBD). Hence, dual targeting of both binding pockets constitutes an attractive alternative molecular entry for pharmacological modulation. Here, we report a chemical biology approach to develop a bitopic ligand for the RORγt NR, enabling concomitant engagement of both binding pockets. Three ca

SUBMITTER: Meijer FA 

PROVIDER: S-EPMC8023582 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature