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

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journal contribution
posted on 16.09.2021, 13:16 by FA Meijer, MCM Van Den Oetelaar, RG Doveston, ENR Sampers, L 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.

Funding

This work was supported by The Netherlands Organization for Scientific Research through Gravity program 024.001.035 and VICI Grant 016.150.366 and the European Union through aMSCA Individual Fellowship (R.G.D., H2020-MSCA-IEF-2016, Grant Number 705188). This work was carried out on the Dutch national e-infrastructure with the support of SURF Cooperative.

History

Citation

ACS Med. Chem. Lett. 2021, 12, 4, 631–639

Author affiliation

School of Chemistry

Version

VoR (Version of Record)

Published in

ACS Medicinal Chemistry Letters

Volume

12

Issue

4

Pagination

631 - 639

Publisher

American Chemical Society (ACS)

issn

1948-5875

eissn

1948-5875

Acceptance date

03/03/2021

Copyright date

2021

Available date

16/09/2021

Language

en