Inhibition of FOXP3 by Stapled Alpha-Helical Peptides Dampens Regulatory T Cell Function
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA828456 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18832632.fastq.gz | Fastqsanger.gz | |||
| SRR18832633.fastq.gz | Fastqsanger.gz | |||
| SRR18832634.fastq.gz | Fastqsanger.gz | |||
| SRR18832635.fastq.gz | Fastqsanger.gz | |||
| SRR18832636.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 12 |
Similar Datasets
Project description:Despite continuing advances in the development of novel cellular-, antibody-, and chemotherapeutic-based strategies to enhance immune reactivity, the presence of regulatory T cells (Tregs) remains a complicating factor to their clinical efficacy. To overcome dosing limitations and off-target effects from antibody-based Treg deletional strategies, we investigated the ability of hydrocarbon stapled alpha-helical (SAH) peptides to target FOXP3, the master transcription factor regulator of Treg development, maintenance, and suppressive function. Using the crystal structure of the FOXP3 homodimer as a guide, we developed SAHs in the likeness of a portion of the native FOXP3 antiparallel coiled-coil homodimerization domain (SAH-FOXP3) to block this key FOXP3 protein-protein interaction (PPI) through molecular mimicry. We show that lead SAH-FOXP3s bind FOXP3, are cell permeable, non-toxic to T cells, induce dose-dependent transcript and protein level alterations of FOXP3 target genes, impede Treg function, and lead to Treg gene expression changes in vivo consistent with Foxp3 dysfunction.
2022-09-29 | GSE201116 | GEO
Project description:The Ras-family small GTPase RAB25 is involved in numerous aspects of endosomal protein trafficking and cell polarity. Recent evidence has established a role for RAB25, as well as related RAB-family and effector proteins, in oncogenic signaling, highlighting the need for chemical probes targeting this class of proteins. Here we report the development of all-hydrocarbon stabilized peptides targeting RAB25 derived from the RAB-binding FIP-family of proteins. Relative to unmodified FIP peptides, optimized stapled peptides show markedly increased structural stability, binding affinity, cell permeability and inhibition of RAB25:FIP complex formation. RAB25 expression has been shown to promote both pro- and anti-oncogenic phenotypes in specific cellular contexts. Stapled peptide RFP14 treatment of breast and ovarian cancer cell lines, in which RAB25 is pro-oncogenic, inhibited migration and proliferation in a RAB25-dependent manner. In contrast, treatment of a triple-negative breast cancer cell line in which RAB25 is tumor suppressive augmented proliferation and migration. Gene expression (RNA Seq) profiling identified significantly altered transcripts in response to RAB25 expression in ovarian cancer cells, and treatment with the optimized stapled peptide RFP14 reversed this expression profile. These data validate first-in-class chemical probes targeting RAB-family proteins and support the role of RAB25 in regulating context-specific oncogenic phenotypes.
2017-07-18 | GSE101528 | GEO
Project description:Excessive Toll-like receptor (TLR) and NF-kB activation during infection causes the overactivation of inflammatory pathways seen in sepsis. Thrombin-derived C-terminal peptides (TCPs) target both bacteria and the resulting TLR-mediated inflammatory response during infection. The present study describes the design and development of a novel multifunctional stapled peptide mimicking the actions of such immunomodulatory TCPs, providing a new drug class based on nature’s own anti-infective strategies. Using a combination of structure-based design, nuclear magnetic resonance spectroscopy (NMR), biophysics, mass spectrometry, microbiology, cellular, and in vivo studies, we describe the development of a structurally locked active stapled form of the endogenous peptide HVFRLKKWIQKVIDQFGE, denoted sHVF18. The stapled peptide shows a higher affinity to CD14 than the linear peptide, retains a partly helical and stabilized structure, and is protease resistant. In vivo, it shows efficacy in experimental models of endotoxin shock in mice and pigs and increases survival in mouse models of polymicrobial sepsis.
2024-01-01 | GSE217695 | GEO
Project description:Stapled peptides are a unique class of cyclic α-helical peptides that are conformationally constrained via their amino acid side-chains. They have been transformative to the field of chemical biology and peptide drug discovery through addressing many of the physicochemical limitations of linear peptides. However, there are several issues with current chemical strategies to produce stapled peptides. For example, two distinct unnatural amino acids are required to synthesize i, i+7 alkene stapled peptides, leading to high production costs. Furthermore, low purified yields are obtained due to cis/trans isomers produced during ring-closing metathesis macrocyclisation. Here we report the development of a new i, i+7 diyne-girder stapling strategy that addresses these issues. The asymmetric synthesis of nine unnatural Fmoc-protected alkyne-amino acids facilitated a systematic study to determine the optimal (S,S)-stereochemistry and 14-carbon diyne-girder bridge length. Diyne-girder stapled T-STAR peptide 29 was demonstrated to have excellent helicity, cell permeability and stability to protease degradation. Finally, we demonstrate that the diyne-girder constraint is a Raman chromophore with potential use in Raman cell microscopy. Development of this highly effective, bifunctional diyne-girder stapling strategy leads us to believe that it can be used to produce other stapled peptide probes and therapeutics.
| S-EPMC10946806 | biostudies-literature
Project description:To investigate effects of Helical multi-walled carbon nanotubes (Helical MWCNTs) on total expression profile of tomato seeds and young sedlings we introduced Helical MWCNTs in MS agar medium in concentrationd of 25 ug/ml. Objectives for this study included the identification of genes that were up or down-regulated at the transcriptional level in tomato seeds and seedlings in response to application of Helical MWCNTs Tomato seeds (1 day after placement of medium) and 11-days old seedlings growing on regular MS agar medium or MS medium supplemented with Helical MWCNTs (25 ug/ml) were selected for RNA extraction and hybridization on Affymetrix microarrays.
2016-05-30 | E-GEOD-70842 | biostudies-arrayexpress
Project description:To investigate effects of Helical multi-walled carbon nanotubes (Helical MWCNTs) on total expression profile of tomato seeds and young sedlings we introduced Helical MWCNTs in MS agar medium in concentrationd of 25 ug/ml. Objectives for this study included the identification of genes that were up or down-regulated at the transcriptional level in tomato seeds and seedlings in response to application of Helical MWCNTs
2016-05-30 | GSE70842 | GEO
Project description: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 ɑ, 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 ɑ 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.
2018-01-09 | GSE108308 | GEO
Project description:BackgroundThe C-terminal domain (CTD) of HIV-1 capsid (CA), like full-length CA, forms dimers in solution and CTD dimerization is a major driving force in Gag assembly and maturation. Mutations of the residues at the CTD dimer interface impair virus assembly and render the virus non-infectious. Therefore, the CTD represents a potential target for designing anti-HIV-1 drugs.ResultsDue to the pivotal role of the dimer interface, we reasoned that peptides from the α-helical region of the dimer interface might be effective as decoys to prevent CTD dimer formation. However, these small peptides do not have any structure in solution and they do not penetrate cells. Therefore, we used the hydrocarbon stapling technique to stabilize the α-helical structure and confirmed by confocal microscopy that this modification also made these peptides cell-penetrating. We also confirmed by using isothermal titration calorimetry (ITC), sedimentation equilibrium and NMR that these peptides indeed disrupt dimer formation. In in vitro assembly assays, the peptides inhibited mature-like virus particle formation and specifically inhibited HIV-1 production in cell-based assays. These peptides also showed potent antiviral activity against a large panel of laboratory-adapted and primary isolates, including viral strains resistant to inhibitors of reverse transcriptase and protease.ConclusionsThese preliminary data serve as the foundation for designing small, stable, α-helical peptides and small-molecule inhibitors targeted against the CTD dimer interface. The observation that relatively weak CA binders, such as NYAD-201 and NYAD-202, showed specificity and are able to disrupt the CTD dimer is encouraging for further exploration of a much broader class of antiviral compounds targeting CA. We cannot exclude the possibility that the CA-based peptides described here could elicit additional effects on virus replication not directly linked to their ability to bind CA-CTD.
| S-EPMC3097154 | biostudies-literature
Project description:Regulatory T cells have been shown to adopt a catabolic metabolic programme with increased capacity for fatty acid oxidation fuelled oxidative phosphorylation (OXPHOS). The role of Foxp3 in this metabolic shift is poorly understood. Here we show that Foxp3 was sufficient to induce a significant increase in the spare respiratory capacity of the cell, the extra OXPHOS capacity available to a cell to increased demands on energy in response to work. Foxp3-expressing cells were enhanced in their ability to utilise palmitate for respiration and in addition the activity of electron transport complexes I, II and IV were enhanced following Foxp3 expression. ATP was secreted by both T effector and regulatory T cells and was reduced by mitochondrial respiration inhibitors. Thus Foxp3 imparts a selective advantage in ATP generation capacity to the cell and may exploit this as a source of adenosine for functional immunomodulation. In order to explore possible mechanisms for these differences in metabolism we conducted a comparative quantitative proteomics study to compare the contribution of TGFβ and the transcription factor Foxp3 to the Treg proteome. We used quantitative mass spectrometry to examine differences between proteomes of nuclear and cytoplasmic Foxp3-containing T cells and Foxp3 positive iTreg and Foxp3 negative activated CD4 T cells in addition to human peripheral blood natural Treg. Gene set enrichment analysis of our proteomic datasets demonstrated that Foxp3 drives a significant up regulation of several members of the mitochondrial electron transport chain.
2017-02-15 | PXD001789 | Pride
Project description:Mitotic chromosome morphogenesis occurs through condensin-mediated disassembly of the interphase conformation and formation of extended prophase loop arrays that then shorten by condensin-dependent helical winding
2018-01-18 | GSE102740 | GEO