SP6 - Estrogen Receptor Stapled Peptide

Nuclear Receptor & Protein Protein Interaction Research Peptides

SP6 is a hydrocarbon-stapled α-helical peptide designed to target estrogen receptors (ERα and ERβ) by mimicking the conserved LXXLL “NR box” motif of nuclear receptor coactivators. This peptide is conformationally stabilized into α-helices, enabling selective binding to the coactivator recognition groove of estrogen receptors. SP6 serves as powerful research tools for investigating nuclear receptor signaling, protein–protein interactions, and transcriptional regulation.

Disease Target

SP6 targets ER+ breast cancer (70% breast cancer), endometrial carcinoma.

Stapling Strategy

SP6 is synthesized by incorporating Fmoc-(S)-2-(4-pentenyl)alanine (Fmoc-(S5)-OH, CAS: 288617-73-2) residues at i,i+4 positions within the LXXLL-containing sequence during solid-phase peptide synthesis (SPPS). The hydrocarbon staple is formed via ruthenium-catalyzed ring-closing olefin metathesis, generating a covalent constraint that stabilizes the α-helical conformation and promotes high-affinity binding to the coactivator-binding groove of estrogen receptors.

Technical specification

	Sequency :	Ac-EKHKIL(S5)RLL(S5)DS-NH2
	MW :	1642.98 g/mol
	Purity :	> 95%
	Counter-Ion :	TFA Salts
	Delivery format :	Lyophilized

Price

Product	Size	Price €	Price $
SB334 - 1mg	1 mg	552	662
SB334 - 5mg	5 mg	701	841
SB334 - 10mg	10 mg	948	1138

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References

J. Am. Chem. Soc. 2011, 133 (24), 9051–9053. https://doi.org/10.1021/ja202946k

Design and Structure of Stapled Peptides Binding to Estrogen Receptors

Abstract

Synthetic peptides that specifically bind nuclear hormone receptors offer an alternative approach to small molecules for the modulation of receptor signaling and subsequent gene expression. Here we describe the design of a series of novel stapled peptides that bind the coactivator peptide site of estrogen receptors. Using a number of biophysical techniques, including crystal structure analysis of receptor–stapled peptide complexes, we describe in detail the molecular interactions and demonstrate that all-hydrocarbon staples modulate molecular recognition events. The findings have implications for the design of stapled peptides in general.

2018 Jan 24;13(3):676–684. doi: 10.1021/acschembio.7b01016

A cell-permeable stapled peptide inhibitor of the estrogen receptor/coactivator interaction

Abstract

We and others have proposed that coactivator binding inhibitors, which block the interaction of estrogen receptor and steroid receptor coactivators, may represent a potential class of new breast cancer therapeutics. The development of coactivator binding inhibitors has been limited, however, because many of the current molecules which are active in in vitro and biochemical assays are not active in cell-based assays. Our goal in this work was to prepare a coactivator binding inhibitor active in cellular models of breast cancer. To accomplish this, we used molecular dynamics simulations to convert a high-affinity stapled peptide with poor cell permeability into R4K1, a cell-penetrating stapled peptide. R4K1 displays high binding affinity for estrogen receptor α, inhibits the formation of estrogen receptor/coactivator complexes, and distributes throughout the cell with a high percentage of nuclear localization. R4K1 represses native gene transcription mediated by estrogen receptor α and inhibits proliferation of estradiol-stimulated MCF-7 cells. Using RNA-Seq, we demonstrate that almost all of the effects of R4K1 on global gene transcription are estrogen receptor-associated. This chemical probe provides a significant proof-of-concept for preparing cell-permeable stapled peptide inhibitors of the estrogen receptor/coactivator interaction.

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