Discovery and development of a new class of drugs: GH antagonists

In attempting to understand the structure of the GH molecule and its function(s), we found that 1 amino acid, glycine, in the third alpha-helix of GH (Gly119 of bovine GH and Gly120 of human GH) was important for biologic activity. Substitution of this glycine residue with a variety of amino acids resulted in GH analogs that lacked growth-promoting activity. More important, these analogs inhibited the actions of GH in vitro and in vivo and were classic antagonists. In this regard, the in vivo expression of GH-antagonist genes in transgenic mice results in dwarf animals that are fertile and have no abnormal phenotypes. The mechanism by which the GH antagonists appear to operate is to inhibit proper or functional GH-receptor dimerization. GH antagonists may have clinical applications when endogenous GH levels are elevated (e.g. acromegaly), or when GH action has been implicated in disease states (e.g., cancer- or diabetes-induced end-organ damage). A GH-receptor antagonist, pegvisomant, has been developed for these clinical situations.