The proinflammatory T helper type 17 (TH17) cells are an important part of the immune armamentarium, but they also have been linked to development of autoimmune diseases such as multiple sclerosis, rheumatoid disease, systemic lupus erythematosus, and inflammatory bowel disease.
The discovery that two nuclear receptors play an important role for the development of this special subset of T cells opened up the possibility that the receptors could be utilized for development of focused therapeutics that inhibit inflammation in general and TH17 cells in particular.
Thomas P. Burris, Ph.D., professor at Scripps Research Institute, and colleagues are studying the retinoic-acid-receptor-related orphan receptors. They developed a high-affinity synthetic ligand to this nuclear receptor that inhibits differentiation and function of TH17 cells.
“TH17 produce several proinflammatory cytokines. Targeting TH17 directly has the advantage of shutting down inflammation rather than attempting to block each individual cytokine. This approach also has an advantage in that it does not interfere with natural T regulatory cells.”
Animal studies performed in Dr. Burris’ lab found that the synthetic compound SR1001 delayed onset and severity in a murine model of autoimmune encephalomyelitis. “These studies have created a lot of excitement in the field. We continue to work with this compound and also have developed others with improved activity that we are studying.”
Dr. Burris is also developing novel ligands for nuclear receptors important for metabolism. “Nuclear receptors have been clearly linked to lipid homeostasis as well as circadian rhythms. We identified and then modified ligands for the REV-ERB family that regulates lipid and glucose metabolism. We found ligands that not only modulated metabolism but also resulted in weight loss. We are looking to see if this could be a treatment for metabolic disorders.”
One serendipitous finding of these studies was that some synthetic compounds also had an effect on behavior. “We found ligands for the REV-ERB family that regulates sleep patterns and others that reduce anxiety. The association of clock genes with these types of behavior may provide new targets for developing novel therapeutics. We are currently looking for partners to license our compounds for clinical development.”
Versatile Estrogen Receptors
Nuclear receptors can be promiscuous, that is, can react with multiple ligands. “I prefer to call that eclectic behavior,” said John A. Katzenellenbogen, professor, department of chemistry, University of Illinois at Urbana-Champaign.
“The estrogen receptor is an example of a receptor that plays diverse roles. Estrogen receptors are rather remarkable in being expressed not only in reproductive tissues such as the uterus and breast but also in the cardiovascular system, the lung, and the brain. This can be helpful or deleterious with regard to therapies. The breast cancer inhibitor tamoxifen blocks the estrogen receptor but unfortunately also stimulates the uterus.
“Our knowledge of the structure and function of nuclear receptors continues to grow. The old lock-and-key concept has evolved to a more sophisticated level in that we are now looking at the cross-talk among receptors and their exquisite ability to accommodate different ligand structures. Using medicinal chemistry approaches, we have found that rather unusual structures can surprisingly result in enhanced selectivity.”
Dr. Katzenellenbogen was recently part of a collaboration with Christopher K. Glass of the University of California School of Medicine, San Diego, that found ligands capable of exerting neuroprotective effects in a subset of estrogen receptors in microglia and astrocytes.
“These cells are found primarily in neural tissue and play a role in the maintenance of homeostasis and responses to infection and cellular injury. We provided a set of our ligands and saw that different ligands affected inflammation differently.
“Aside from in vitro assays, these neuroprotective effects extended to an animal model of multiple sclerosis—i.e., murine experimental autoimmune encephalomyelitis. We hope to continue studies with these ligands that we feel have a potential for therapeutic development.”
Dr. Katzenellenbogen cautioned that “overall, these studies show how specific chemical modifications in ligands can have different effects for the better or for the worse. Ultimately, as we better understand how ligands fit into their various receptors, we hope to be able to design improved drugs with reduced untoward effects.”