High Throughput Screening for Ligands for Seven Transmembrane-spanning Receptors

National Institute Of Diabetes And Digestive And Kidney Diseases

Investigators

Linked publications, trials & patents

Abstract

Seven transmembrane-spanning receptors (7TMRs or G protein-coupled receptors, GPCRs) represent the largest family of signal-transducing molecules known. 7TMRs convey signals for light and many extracellular regulatory molecules, such as, hormones, growth factors and neurotransmitters, that regulate every cell in the body. Dysregulation of 7TMRs has been found in a growing number of human diseases and 7TMRs have been estimated to be the targets of more than 30% of the drugs used in clinical medicine today. Thus, discovery of probes/drugs for 7TMRs is an important goal of biomedical research. We use high throughput screening (HTS) for small molecule ligands (SMLs) for 7TMRs with the receptors for thyroid-stimulating hormone (TSH-R) and thyrotropin-releasing hormone (TRH-R). During this year, we continued our development of these SMLs. 1) We showed that one of our SML TSHR agonists was able to activate TSHR mutants that are found in patients with a rare form of hypothyroidism. This showed conclusively that the cause of hypothyroidism in these patients was due to the inability of these mutant receptors to bind TSH. 2) We used a SML antagonist for the TSH-R in cells obtained from the orbital tissue of patients with Graves' ophthalmopathy to show that TSHRs on these cells could be inhibited. This is a proof-of-principle that a drug to treat the ophthalmopathy of Graves' disease in humans may be developed. 3) We showed that a SML antagonist of TSH-R was able to inhibit TSH-R activation in the cells from the orbits of Graves' ophthalmopathy patients by thyroid-stimulating antibodies that are the cause of Graves' disease. Thus, further supporting the idea that SMLs could be developed into drugs to treat these patients. 4) We were invited to write an update article on our SMLs for the TSH-R for the Journal of Clinical Endocrinology and Metabolism.