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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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).

Author information

Affiliations

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

    • Naresh Kumar
    • , Monica A. Istrate
    • , Dušica Vidović
    • , Stephan C. Schürer
    •  & Patrick R. Griffin
  3. Department of Chemistry, The Scripps Research Institute, Jupiter, Florida 33458, USA

    • Philippe Nuhant
    •  & William R. Roush
  4. The Translational Research Institute, The Scripps Research Institute, Jupiter, Florida 33458, USA

    • Theodore M. Kamenecka
    •  & Patrick R. Griffin
  5. Center for Computational Science University of Miami, Miami, Florida 33136, USA

    • Dušica Vidović
    •  & Stephan C. Schürer
  6. Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA

    • Jihong Xu
    • , Gail Wagoner
    •  & Paul D. Drew

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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.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Thomas P. Burris.

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DOI

https://doi.org/10.1038/nature10075

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