Covalent Occlusion of the RORγt Ligand Binding Pocket Allows Unambiguous Targeting of an Allosteric Site

Femke A. Meijer, M.C.M. van den Oetelaar, R.G. Doveston, E.N.R. Sampers, Lucas Brunsveld (Corresponding author)

Onderzoeksoutput: Bijdrage aan tijdschriftTijdschriftartikelAcademicpeer review

Samenvatting

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.
Originele taal-2Engels
Pagina's (van-tot)631-639
Aantal pagina's9
TijdschriftACS Medicinal Chemistry Letters
Volume12
Nummer van het tijdschrift4
DOI's
StatusGepubliceerd - 8 apr 2021

Vingerafdruk Duik in de onderzoeksthema's van 'Covalent Occlusion of the RORγt Ligand Binding Pocket Allows Unambiguous Targeting of an Allosteric Site'. Samen vormen ze een unieke vingerafdruk.

Citeer dit