The implementation of small molecule agonists and antagonists to elucidate gonadotropin receptor structure, function and physiology

Abstract

Pursuant to patient desires of alternatives to injectable gonadotropins, a plethora of attempts have identified, characterized, and demonstrated efficacy of small molecules that activate (agonists) gonadotropin receptors. Discoveries have also been made of small molecule gonadotropin receptor inhibitors (antagonists), which have potential as useful alternatives to steroid hormone-based contraception. Implementation of these small molecules in advanced testing systems not necessarily used in screening, which identified lead compounds, has yielded a bounty of wonders. It is likely that a richer understanding of the role of signaling platforms and conformation-dependent molecular assemblies are likely to emerge. Several small molecule agonists have been observed to function as conformational boosters that can rescue receptor trafficking defects, or initiate internalization of receptors without bound hormone. Still others have revealed insights into the role of molecular platforms in persistent signaling. Unexpectedly, such antagonists, like molecular scalpels, can ablate certain signaling pathways and not others leading to discovery of biased signaling in gonadotropin receptors. That seminal observation has led to studies of nuanced signaling and, consequently, nuanced gene expression. Gonadotropin receptor structure-based design for better specificity and potency of agonists and antagonists has been provided by new cryo-EM structures of the gonadotropin receptors, demonstrating proof of concept. Structural determination of downstream supramolecular assemblies will be necessary to validate and fully understand these complicated receptors and how their interaction with other proteins and when occupied by hormone and allosteric modulators, nuances their actions and, ultimately, fertility.

HIGHLIGHTS • Small molecules that bind to gonadotropin receptors may activate or inhibit receptor function. • The majority of small molecules for the gonadotropin receptors are allosteric compounds. • Some agonists and antagonists exhibit biased signaling and/or promote correct folding and trafficking defects. • Though not in clinical use, they have helped decode receptor structure and function. • Gonadotropin receptor small molecules offer alternatives for more precise and nuanced fertility modulation.