Estradiol (E2) and the oestrogen receptor-alpha (ERα) signalling pathway play pivotal roles in the proliferative activity of breast cancer cells. Recent findings show that the brefeldin A-inhibited guanine nucleotide-exchange protein 3-prohibitin 2 (BIG3-PHB2) complex plays a crucial role in E2/ERα signalling modulation in breast cancer cells. Moreover, specific inhibition of the BIG3-PHB2 interaction using the ERα activity-regulator synthetic peptide (ERAP: 165–177 amino acids), derived from α-helical BIG3 sequence, resulted in a significant anti-tumour effect. However, the duration of this effect was very short for viable clinical application. We developed the chemically modified ERAP using stapling methods (stapledERAP) to improve the duration of its antitumour effects. The stapledERAP specifically inhibited the BIG3-PHB2 interaction and exhibited long-lasting suppressive activity. Its intracellular localization without the membrane-permeable polyarginine sequence was possible via the formation of a stable α-helix structure by stapling. Tumour bearing-mice treated daily or weekly with stapledERAP effectively prevented the BIG3-PHB2 interaction, leading to complete regression of E2-dependent tumours in vivo. Most importantly, combination of stapledERAP with tamoxifen, fulvestrant, and everolimus caused synergistic inhibitory effects on growth of breast cancer cells. Our findings suggested that the stapled ERAP may be a promising anti-tumour drug to suppress luminal-type breast cancer growth.
A practical and efficient methodology for the chemical synthesis of peptides/proteins using a one-pot/sequential ligation is described. It features the use of photocleavable S-protection on an N-sulfanylethylaniline moiety. Removal of the S-protecting ligated materials under UV irradiation provides a readily usable mixture for subsequent native chemical ligation.
Bridged peptides including stapled peptides are attractive tools for regulating protein-protein interactions (PPIs). An effective synthetic methodology in a heterogeneous system for the preparation of these peptides using olefin metathesis and hydrogenation of protected peptides with a long aliphatic chain anchor is reported.
Inhibition of lysine-specific demethylase 1 (LSD1), a flavin-dependent histone demethylase, has recently emerged as a new strategy for treating cancer and other diseases. LSD1 interacts physically with SNAIL1, a member of the SNAIL/SCRATCH family of transcription factors. This study describes the discovery of SNAIL1 peptide-based inactivators of LSD1. We designed and prepared SNAIL1 peptides bearing a propargyl amine, hydrazine, or phenylcyclopropane moiety. Among them, peptide 3, bearing hydrazine, displayed the most potent LSD1-inhibitory activity in enzyme assays. Kinetic study and mass spectrometric analysis indicated that peptide 3 is a mechanism-based LSD1 inhibitor. Furthermore, peptides 37 and 38, which consist of cell-membrane-permeable oligoarginine conjugated with peptide 3, induced a dose-dependent increase of dimethylated Lys4 of histone H3 in HeLa cells, suggesting that they are likely to exhibit LSD1-inhibitory activity intracellularly. In addition, peptide 37 decreased the viability of HeLa cells. We believe this new approach for targeting LSD1 provides a basis for development of potent selective inhibitors and biological probes for LSD1.
We describe a novel peptide ligation/desulfurization strategy using a β-mercapto-N-glycosylated asparagine derivative. The newly developed procedure was successfully applied to the total chemical synthesis of the GM2 ganglioside activator protein bearing a monosaccharide on the native glycosylation site.
A novel, recyclable, thiourea-based asymmetric organocatalyst containing a hydrophobic anchor has been developed. The chemical nature of the hydrophobic anchor contributes to the desirable characteristics of the recyclable catalyst. The hydrophobic anchor-tagged thiourea catalyst is highly soluble in less polar solvents, which is compatible with amino thiourea catalyst-mediated asymmetric reaction conditions, but sparingly soluble in polar solvents used for the recycle process. This asymmetric catalyst delivers a catalytic performance comparable to that of a parent catalyst and can be readily recycled from reactions.Access to a wide variety of chiral compounds requires that asymmetric catalysts perform well in the construction of chiral centers. Amongst known efficient asymmetric catalysts, organocatalysts have attracted attention increasingly because they are cost-effective, less toxic, and operationally simple compared with conventional metal catalysts. [1] Amino thiourea catalysts are dual-activating organocatalysts which simultaneously activate both an electrophile and a nucleophile in a highly enantioselective reaction, affording a chiral product. [2] For example, Takemoto's thiourea catalyst 1 has been applied to a variety of asymmetric reactions ( Figure 1). [2c] In comparison with the asymmetric metal catalysts, a weak point of organocatalysts is that relatively large amounts of the catalyst load must be used. Because of this, recyclable organocatalysts have been designed to extend the synthetic utility of organocatalysts. [3] Recyclable thiourea catalysts that have been developed to date have an insoluble resin support, [4a,b] a polyethylene glycol (PEG) moiety, [4a] or a fluorocarbon carrier [4c,d] as shown in Figure 1. A poly styrene-type insoluble resin support in a catalyst 2 allows for easy recovery of the catalyst from a reaction, typically by filtration, but the two-phase reaction using a resin-supported catalyst generally results in reduced catalytic activity. PEG as a carrier can be used in solution and leads to a more favorable reaction outcome. A drawback of PEG catalysts such as 3 is that difficulties in the control of the solubility can lead to low efficiency in the recovery. Recently, catalysts 4 and 5 with a perfluoroalkyl chain were independently developed by Cai [4c] and Miura. [4d] Such fluorine-containing catalysts have a high affinity for fluorinecontaining solvents or silica gel. These features allow the fluoroalkyl catalyst to be separated by extractive or chromatographic work-up using fluorine-containing solvent. Such solvents may however be expensive.In this context, we envisioned that the use of a hydrophobic anchor tag consisting of an extended alkyl chain as a carrier could be used in the development of a novel recyclable catalyst which can overcome the drawbacks mentioned above. Hydrophobic anchors have been independently developed by Tamiaki and Chiba and Takahashi for use in peptide synthesis. [5] Generally, such anchors enhance the solubility of the tagged molecu...
A photoresponsive amide cleavage device was developed based on the asparagine imidation-mediated cleavage of peptide bonds during intein-mediated protein splicing. The chemical environment of the protein splicing process was mimicked by the incorporation of geminal dimethyl groups and a secondary amine unit in asparagine scaffold. Furthermore, the resulting photoresponsive device could induce the phototriggered cleavage of an amide bond by the protection of the secondary amine unit with an o-nitrobenzyloxycarbonyl group.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.