title: ACTH Antagonists.
abstract: Adrenocorticotropin (ACTH) acts via a highly selective receptor that is a member of the melanocortin receptor subfamily of type 1 G protein-coupled receptors. The ACTH receptor, also known as the melanocortin 2 receptor (MC2R), is unusual in that it is absolutely dependent on a small accessory protein, melanocortin receptor accessory protein (MRAP) for cell surface expression and function. ACTH is the only known naturally occurring agonist for this receptor. This lack of redundancy and high degree of ligand specificity suggests that antagonism of this receptor could provide a useful therapeutic aid and a potential investigational tool. Clinical situations in which this could be useful include (1) Cushing's disease and ectopic ACTH syndrome - especially while preparing for definitive treatment of a causative tumor, or in refractory cases, or (2) congenital adrenal hyperplasia - as an adjunct to glucocorticoid replacement. A case for antagonism in other clinical situations in which there is ACTH excess can also be made. In this article, we will explore the scientific and clinical case for an ACTH antagonist, and will review the evidence for existing and recently described peptides and modified peptides in this role.
authors.affiliation: Centre for Endocrinology, William Harvey Research Institute, Queen Mary University of London , London , UK.
authors.forename: Adrian John
authors.initials: AJ
authors.lastname: Clark
authors.affiliation: Centre for Therapeutics Discovery, MRC Technology , Stevenage , UK.
authors.forename: Rachel
authors.initials: R
authors.lastname: Forfar
authors.affiliation: Centre for Endocrinology, William Harvey Research Institute, Queen Mary University of London , London , UK.
authors.forename: Mashal
authors.initials: M
authors.lastname: Hussain
authors.affiliation: Centre for Therapeutics Discovery, MRC Technology , Stevenage , UK.
authors.forename: Jeff
authors.initials: J
authors.lastname: Jerman
authors.affiliation: Centre for Therapeutics Discovery, MRC Technology , Stevenage , UK.
authors.forename: Ed
authors.initials: E
authors.lastname: McIver
authors.affiliation: Centre for Therapeutics Discovery, MRC Technology , Stevenage , UK.
authors.forename: Debra
authors.initials: D
authors.lastname: Taylor
authors.affiliation: Centre for Endocrinology, William Harvey Research Institute, Queen Mary University of London , London , UK.
authors.forename: Li
authors.initials: L
authors.lastname: Chan
keywords: Cushing’s syndrome; G protein-coupled receptor; adrenocorticotropin hormone; congenital adrenal hyperplasia; high throughput screening; peptide hormone antagonists; receptor antagonism; receptor modelling