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

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 l...

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Autores principales:	Suzanne G. Mays, Józef Stec, Xu Liu, Emma H. D’Agostino, Richard J. Whitby, Eric A. Ortlund
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/bde5e80a95114cbbb7800f850e004f61
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spelling	oai:doaj.org-article:bde5e80a95114cbbb7800f850e004f612021-12-02T13:34:01ZEnantiomer-specific activities of an LRH-1 and SF-1 dual agonist10.1038/s41598-020-79251-92045-2322https://doaj.org/article/bde5e80a95114cbbb7800f850e004f612020-12-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-79251-9https://doaj.org/toc/2045-2322Abstract 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.Suzanne G. MaysJózef StecXu LiuEmma H. D’AgostinoRichard J. WhitbyEric A. OrtlundNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-14 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Suzanne G. Mays Józef Stec Xu Liu Emma H. D’Agostino Richard J. Whitby Eric A. Ortlund Enantiomer-specific activities of an LRH-1 and SF-1 dual agonist
description	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.
format	article
author	Suzanne G. Mays Józef Stec Xu Liu Emma H. D’Agostino Richard J. Whitby Eric A. Ortlund
author_facet	Suzanne G. Mays Józef Stec Xu Liu Emma H. D’Agostino Richard J. Whitby Eric A. Ortlund
author_sort	Suzanne G. Mays
title	Enantiomer-specific activities of an LRH-1 and SF-1 dual agonist
title_short	Enantiomer-specific activities of an LRH-1 and SF-1 dual agonist
title_full	Enantiomer-specific activities of an LRH-1 and SF-1 dual agonist
title_fullStr	Enantiomer-specific activities of an LRH-1 and SF-1 dual agonist
title_full_unstemmed	Enantiomer-specific activities of an LRH-1 and SF-1 dual agonist
title_sort	enantiomer-specific activities of an lrh-1 and sf-1 dual agonist
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/bde5e80a95114cbbb7800f850e004f61
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Enantiomer-specific activities of an LRH-1 and SF-1 dual agonist

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