Summary assay for small molecule antagonists of the EBI2 receptor
Epstein-Barr virus-induced gene 2 (EBI2) (1-4), also known as GPR183, is expressed on B cells and is highly induced upon activation (5). Recent gene targeting experiments revealed that EBI2-/- B cells exhibited defective migration, resulting in strongly impaired T cell-dependent antibody responses (1, 2). Most recently, two research teams made the unlikely discovery that oxysterol compounds, more ..
Data Source: Sanford-Burnham Center for Chemical Genomics (SBCCG)
Source Affiliation: Sanford-Burnham Medical Research Institute(SBMRI, San Diego, CA)
Network: NIH Molecular Libraries Probe Production Centers Network (MLPCN)
Grant Number: 1 R03 MH097522-01
Assay Provider: Robert Rickert, Ph.D., Sanford-Burnham Medical Research Institute
Epstein-Barr virus-induced gene 2 (EBI2) (1-4), also known as GPR183, is expressed on B cells and is highly induced upon activation (5). Recent gene targeting experiments revealed that EBI2-/- B cells exhibited defective migration, resulting in strongly impaired T cell-dependent antibody responses (1, 2). Most recently, two research teams made the unlikely discovery that oxysterol compounds, previously known to bind nuclear receptors, are the physiologic ligands for EBI2 (3, 4). Although other closely related oxysterols showed some potency and binding capability to EBI2, the most potent endogenous EBI2 receptor ligand and activator was 7alpha,25-dihydroxycholesterol (7alpha,25-OHC) (4). EBI2-/- B cells did not bind 7alpha,25-OHC and mice deficient for cholesterol 25-hydroxylase that is necessary to generate 7alpha,25-OHC display a phenotype similar to that of EBI2-/- mice (3). The recent publication in July 2011 of the deorphanizing of this receptor is a major step forward towards understanding the role of EBI2 in immunobiology. In order to investigate the importance of EBI2 in immune processes and potential as a drug target, selective potent chemical probes that antagonize this receptor need to be identified and made freely available to the research community.
The probes sought will be identified and optimized based on their ability to antagonize this receptor in functional cellular systems, with the ultimate objective of generating compounds that will function in vivo. Armed with such tools a full examination of the consequences of antagonizing this receptor in well characterized ex vivo murine and human models of the immune system will be possible. Antagonists would be anticipated to not only blunt antibody production but may also have more broad reaching effects on inflammation. Prospectively, these probes could be used to investigate the role of this receptor in mouse models of autoantibody-dependent inflammatory disease such as rheumatoid arthritis and lupus, or more broadly applied to examine effects on systemic inflammation.
1. Gatto D, Paus D, Basten A, Mackay CR, Brink R. Guidance of B cells by the orphan G protein-coupled receptor EBI2 shapes humoral immune responses. Immunity. 2009;31(2):259-69.
2. Pereira JP, Kelly LM, Xu Y, Cyster JG. EBI2 mediates B cell segregation between the outer and centre follicle. Nature. 2009;460(7259):1122-6. PMCID: 2809436.
3. Hannedouche S, Zhang J, Yi T, Shen W, Nguyen D, Pereira JP, et al. Oxysterols direct immune cell migration via EBI2. Nature. 2011;475(7357):524-7.
4. Liu C, Yang XV, Wu J, Kuei C, Mani NS, Zhang L, et al. Oxysterols direct B-cell migration through EBI2. Nature. 2011;475(7357):519-23.
5. Chan TD, Gardam S, Gatto D, Turner VM, Silke J, Brink R. In vivo control of B-cell survival and antigen-specific B-cell responses. Immunological Reviews. 2010;237(1):90-103.
Probe molecules are defined as the positives of this assay and assigned a score of 100. Testing has not progressed to the point where a probe molecule has been identified.