Enantiomer-specific activities of an LRH-1 and SF-1 dual agonist

• Type of Material: Article
• Authors: Suzanne G. Mays, Emory University; Józef Stec, University of Southampton; Xu Liu, Emory University; Emma H. D'Agostino, Emory University; Richard J. Whitby, University of Southampton; Eric Ortlund, Emory University
• Language: English
• Date: 2020-12-17
• Publisher: NATURE RESEARCH
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2020
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41598-020-79251-9
• Title of Journal or Parent Work: SCIENTIFIC REPORTS
• Volume: 10
• Issue: 1
• Start Page: 22279
• End Page: 22279
• Grant/Funding Information: This work was supported by the National Institutes of Health National Institute of General Medical Sciences [Grant T32-GM008602 to SGM], National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant F31-DK111171 to SGM, Grants R01-DK095750 and R01-DK114213 to EAO], the National Science Foundation [Grant DGE-1444932 to EHD], the American Heart Association [Grant 17POST33660110 to XL], and an Emory Catalyst Grant to EAO. RJW and JS thank GlaxoSmithKline for generous funding.
• Keywords: Science & Technology - Other Topics; Science & Technology; PROTECTS; SUMOYLATION; DYNAMICS; Multidisciplinary Sciences; ANTAGONISTS; REVEAL; GLUCOCORTICOID SYNTHESIS; EXPRESSION; LIVER RECEPTOR HOMOLOG-1; NR5A2; METABOLISM
• Research Categories: Health Sciences, Nutrition; Chemistry, Pharmaceutical; Chemistry, Biochemistry

Abstract

Chirality is an important consideration in drug development: it can influence recognition of the intended target, pharmacokinetics, and off-target effects. Here, we investigate how chirality affects the activity and mechanism of action of RJW100, a racemic agonist of the nuclear receptors liver receptor homolog-1 (LRH-1) and steroidogenic factor-1 (SF-1). LRH-1 and SF-1 modulators are highly sought as treatments for metabolic and neoplastic diseases, and RJW100 has one of the few scaffolds shown to activate them. However, enantiomer-specific effects on receptor activation are poorly understood. We show that the enantiomers have similar binding affinities, but RR-RJW100 stabilizes both receptors and is 46% more active than SS-RJW100 in LRH-1 luciferase reporter assays. We present an LRH-1 crystal structure that illuminates striking mechanistic differences: SS-RJW100 adopts multiple configurations in the pocket and fails to make an interaction critical for activation by RR-RJW100. In molecular dynamics simulations, SS-RJW100 attenuates intramolecular signalling important for coregulator recruitment, consistent with previous observations that it weakly recruits coregulators in vitro. These studies provide a rationale for pursuing enantiomerically pure RJW100 derivatives: they establish RR-RJW100 as the stronger LRH-1 agonist and identify a potential for optimizing the SS-RJW100 scaffold for antagonist design.