Targeting Orphan Receptors for Multiple Sclerosis

Share

ROR-alpha ligand binding domain
Crystal structure of the ligand-binding domain of RORα complexed with cholesterol sulfate. PDB ID=1S0X
Scientists at the Scripps Research Institute have reported on compounds that are able to suppress severity and disease progression in animal models of multiple sclerosis. The compounds, exemplified by SR1001, act by selectively suppressing a subset of T-helper cells characterised by their production of interleukin-17 (TH17 cells). TH17 cells have been implicated in a variety of autoimmune diseases including rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease and systemic lupus erythematosus.

SR1001 selectively binds to two orphan nuclear receptors: retinoic acid receptor-related orphan receptors α and γt (RORα and RORγt). These receptors have indispensible roles in the development and function of TH17 cells, providing a mechanism for modulating one component of the immune system without general immunosuppression. The team reports that SR1001 induces a conformational change in the receptors that results in their reduced affinity for co-activators and increased affinity for co-repressors. The net result is inhibition of the receptors’ transcriptional activity.

SR1001 blocked the development of murine TH17 cells and inhibited cytokine production by differentiated murine and human TH17 cells. Although a drug is some way off, the team suggests that the results demonstrate the feasibility of targeting TH17 cells and the potential of such an approach for the treatment of autoimmune diseases.

The study is published in Nature.

2 thoughts on “Targeting Orphan Receptors for Multiple Sclerosis”

  1. A solid tool for examining the pathophysiology of a compound disease is the identification of underlying genetic controls. Numerous genes have been caught up as contributing to the risk of developing MS.

  2. Newly published results have proved that the levels of some chemokines and chemokine receptors are increased in blood and cerebrospinal fluid of MS patients.

Leave a Reply

Your email address will not be published. Required fields are marked *