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Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand

Nature volume 472, pages 491–494 (2011)Cite this article

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Abstract

T-helper cells that produce interleukin-17 (TH17 cells) are a recently identified CD4+ T-cell subset with characterized pathological roles in autoimmune diseases1,2,3. The nuclear receptors retinoic-acid-receptor-related orphan receptors α and γt (RORα and RORγt, respectively) have indispensible roles in the development of this cell type4,5,6,7. Here we present SR1001, a high-affinity synthetic ligand—the first in a new class of compound—that is specific to both RORα and RORγt and which inhibits TH17 cell differentiation and function. SR1001 binds specifically to the ligand-binding domains of RORα and RORγt, inducing a conformational change within the ligand-binding domain that encompasses the repositioning of helix 12 and leads to diminished affinity for co-activators and increased affinity for co-repressors, resulting in suppression of the receptors’ transcriptional activity. SR1001 inhibited the development of murine TH17 cells, as demonstrated by inhibition of interleukin-17A gene expression and protein production. Furthermore, SR1001 inhibited the expression of cytokines when added to differentiated murine or human TH17 cells. Finally, SR1001 effectively suppressed the clinical severity of autoimmune disease in mice. Our data demonstrate the feasibility of targeting the orphan receptors RORα and RORγt to inhibit specifically TH17 cell differentiation and function, and indicate that this novel class of compound has potential utility in the treatment of autoimmune diseases.

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Figure 1: SR1001 is a selective RORα and RORγ inverse agonist.
Figure 2: SR1001 modulates the expression of ROR target genes by decreasing co-activator recruitment.
Figure 3: SR1001 inhibits the expression of cytokines expressed by T H 17 cells.
Figure 4: SR1001 inhibits T H 17 cell development and IL-17A secretion.

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Acknowledgements

This work was supported by NIH grants to T.P.B. (DK080201, DK089984 and MH084512), to L.A.S. (DK088499) and P.R.G. (GM084041) and a grant from the National Multiple Sclerosis Society to P.D.D. (RG389A2/1). Additionally, the efforts of P.R.G. and W.R.R. were supported by the NIH Molecular Library Screening Center Network (MLSCN) grant U54MH074404 (Hugh Rosen, Principal Investigator).

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Authors and Affiliations

  1. Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, 33458, Florida, USA

    Laura A. Solt, Naresh Kumar, Yongjun Wang, Janelle L. Lauer, Jin Liu, Monica A. Istrate, Patrick R. Griffin & Thomas P. Burris

  2. The Scripps Research Institute Molecular Screening Center, The Scripps Research Institute, Jupiter, 33458, Florida, USA

    Naresh Kumar, Monica A. Istrate, Dušica Vidović, Stephan C. Schürer & Patrick R. Griffin

  3. Department of Chemistry, The Scripps Research Institute, Jupiter, 33458, Florida, USA

    Philippe Nuhant & William R. Roush

  4. The Translational Research Institute, The Scripps Research Institute, Jupiter, 33458, Florida, USA

    Theodore M. Kamenecka & Patrick R. Griffin

  5. Center for Computational Science University of Miami, Miami, 33136, Florida, USA

    Dušica Vidović & Stephan C. Schürer

  6. Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, 72205, Arkansas, USA

    Jihong Xu, Gail Wagoner & Paul D. Drew

Authors
  1. Laura A. Solt
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Contributions

P.R.G. and T.P.B. conceived the project. L.A.S., P.R.G. and T.P.B. planned the project. Medicinal chemistry was planned and performed by P.N., T.M.K. and W.R.R. Biochemical and cell based assays were performed by L.A.S., N.K., Y.W., J.L. and M.A.I. Molecular modelling was performed by D.V. and S.C.C. The EAE model was designed and performed by J.X., G.W. and P.D.D. HDX studies were performed by J.L.L. The manuscript was written by L.A.S. and T.P.B.

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Correspondence to Thomas P. Burris.

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The authors declare no competing financial interests.

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Solt, L., Kumar, N., Nuhant, P. et al. Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand. Nature 472, 491–494 (2011). https://doi.org/10.1038/nature10075

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