Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Identification of novel inhibitors that disrupt STAT3-DNA interaction from a ?-AApeptide OBOC combinatorial library.

ABSTRACT: From a ?-AApeptide-based one-bead-one-compound (OBOC) combinatorial library, we identified ?-AApeptides that can selectively inhibit STAT3-DNA interaction and suppress the expression levels of STAT3 target genes in intact cells. Our results demonstrate that in addition to the SH2 domain, the DNA binding domain of STAT3 is targetable for the development of a new generation of anti-cancer therapeutics.

SUBMITTER: Teng P

PROVIDER: S-EPMC4128407 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Identification of novel inhibitors that disrupt STAT3-DNA interaction from a γ-AApeptide OBOC combinatorial library.

Teng Peng P Zhang Xiaolei X Wu Haifan H Qiao Qiao Q Sebti Said M SM Cai Jianfeng J

Chemical communications (Cambridge, England) 20140625 63

From a γ-AApeptide-based one-bead-one-compound (OBOC) combinatorial library, we identified γ-AApeptides that can selectively inhibit STAT3-DNA interaction and suppress the expression levels of STAT3 target genes in intact cells. Our results demonstrate that in addition to the SH2 domain, the DNA binding domain of STAT3 is targetable for the development of a new generation of anti-cancer therapeutics. ...[more]

PMID: 24964402

Similar Datasets

One-Bead-Two-Compound Thioether Bridged Macrocyclic γ-AApeptide Screening Library against EphA2.

Project description:Identification of molecular ligands that recognize peptides or proteins is significant but poses a fundamental challenge in chemical biology and biomedical sciences. Development of cyclic peptidomimetic library is scarce, and thus discovery of cyclic peptidomimetic ligands for protein targets is rare. Herein we report the unprecedented one-bead-two-compound (OBTC) combinatorial library based on a novel class of the macrocyclic peptidomimetics γ-AApeptides. In the library, we utilized the coding peptide tags synthesized with Dde-protected α-amino acids, which were orthogonal to solid phase synthesis of γ-AApeptides. Employing the thioether linkage, the desired macrocyclic γ-AApeptides were found to be effective for ligand identification. Screening the library against the receptor tyrosine kinase EphA2 led to the discovery of one lead compound that tightly bound to EphA2 (Kd = 81 nM) and potently antagonized EphA2-mediated signaling. This new approach of macrocyclic peptidomimetic library may lead to a novel platform for biomacromolecular surface recognition and function modulation.

| S-EPMC5881388 | biostudies-literature

Inhibition of β-catenin/B cell lymphoma 9 protein-protein interaction using α-helix-mimicking sulfono-γ-AApeptide inhibitors.

Project description:The rational design of α-helix-mimicking peptidomimetics provides a streamlined approach to discover potent inhibitors for protein-protein interactions (PPIs). However, designing cell-penetrating long peptidomimetic scaffolds equipped with various functional groups necessary for interacting with large protein-binding interfaces remains challenging. This is particularly true for targeting β-catenin/BCL9 PPIs. Here we designed a series of unprecedented helical sulfono-γ-AApeptides that mimic the binding mode of the α-helical HD2 domain of B Cell Lymphoma 9 (BCL9). Our studies show that sulfono-γ-AApeptides can structurally and functionally mimic the α-helical domain of BCL9 and selectively disrupt β-catenin/BCL9 PPIs with even higher potency. More intriguingly, these sulfono-γ-AApeptides can enter cancer cells, bind with β-catenin and disrupt β-catenin/BCL9 PPIs, and exhibit excellent cellular activity, which is much more potent than the BCL9 peptide. Furthermore, our enzymatic stability studies demonstrate the remarkable stability of the helical sulfono-γ-AApeptides, with no degradation in the presence of pronase for 24 h, augmenting their biological potential. This work represents not only an example of helical sulfono-γ-AApeptides that mimic α-helix and disrupt protein-protein interactions, but also an excellent example of potent, selective, and cell-permeable unnatural foldameric peptidomimetics that disrupt the β-catenin/BCL9 PPI. The design of helical sulfono-γ-AApeptides may lead to a new strategy to modulate a myriad of protein-protein interactions.

| S-EPMC6561201 | biostudies-literature

Design of inhibitors using a combinatorial library for HIV-Nef and human SH3 domain interaction.

Project description:The HIV-1 Nef protein has the ability to down regulate important molecules at the immune synapse. These include class I and class II (Human Leukocyte Antigen) HLA on the Antigen Presenting Cells (APC). The receptors in these molecules consist of SH-3 domain and their interaction with the HIV-1 Nef is critical. Therefore, it is important to inhibit this HIV-Nef and human SH3 domain interaction. Thus, we used a combinatorial library to screen for molecules to inhibit this interaction. The exercise identified a group of top ranking compounds for further consideration.

| S-EPMC3766310 | biostudies-literature

α-Helix-Mimicking Sulfono-γ-AApeptide Inhibitors for p53-MDM2/MDMX Protein-Protein Interactions.

Project description:The use of peptidomimetic scaffolds is a promising strategy for the inhibition of protein-protein interactions (PPIs). Herein, we demonstrate that sulfono-γ-AApeptides can be rationally designed to mimic the p53 α-helix and inhibit p53-MDM2 PPIs. The best inhibitor, with Kd and IC50 values of 26 nM and 0.891 μM toward MDM2, respectively, is among the most potent unnatural peptidomimetic inhibitors disrupting the p53-MDM2/MDMX interaction. Using fluorescence polarization assays, circular dichroism, nuclear magnetic resonance spectroscopy, and computational simulations, we demonstrate that sulfono-γ-AApeptides adopt helical structures resembling p53 and competitively inhibit the p53-MDM2 interaction by binding to the hydrophobic cleft of MDM2. Intriguingly, the stapled sulfono-γ-AApeptides showed promising cellular activity by enhancing p53 transcriptional activity and inducing expression of MDM2 and p21. Moreover, sulfono-γ-AApeptides exhibited remarkable resistance to proteolysis, augmenting their biological potential. Our results suggest that sulfono-γ-AApeptides are a new class of unnatural helical foldamers that disrupt PPIs.

| S-EPMC7025332 | biostudies-literature

Cell-Permeable Bicyclic Peptidyl Inhibitors against NEMO-I?B Kinase Interaction Directly from a Combinatorial Library.

Project description:Macrocyclic peptides are capable of binding to flat protein surfaces such as the interfaces of protein-protein interactions with antibody-like affinity and specificity, but generally lack cell permeability in order to access intracellular targets. In this work, we designed and synthesized a large combinatorial library of cell-permeable bicyclic peptides, in which the first ring consisted of randomized peptide sequences for potential binding to a target of interest, while the second ring featured a family of different cell-penetrating motifs, for both cell penetration and target binding. The library was screened against the I?B kinase ?/? (IKK?/?)-binding domain of NF-?B essential modulator (NEMO), resulting in the discovery of several cell-permeable bicyclic peptides, which inhibited the NEMO-IKK? interaction with low ?M IC50 values. Further optimization of one of the hits led to a relatively potent and cell-permeable NEMO inhibitor (IC50 = 1.0 ?M), which selectively inhibited canonical NF-?B signaling in mammalian cells and the proliferation of cisplatin-resistant ovarian cancer cells. The inhibitor provides a useful tool for investigating the biological functions of NEMO/NF-?B and a potential lead for further development of a novel class of anti-inflammatory and anticancer drugs.

| S-EPMC6231237 | biostudies-literature

Identification of Potent hDHODH Inhibitors for Lung Cancer via Virtual Screening of a Rationally Designed Small Combinatorial Library.

Project description:Cancer is characterized by altered cellular metabolism, and metabolic enzymes are considered as a promising target for anticancer therapy. Pyrimidine metabolism dysregulation is associated with various types of cancer, particularly lung cancer, which is one of the leading causes of cancer-related mortality worldwide. Recent studies have shown that small-cell lung cancer cells are particularly reliant on the pyrimidine biosynthesis pathway and are sensitive to its disruption. DHODH, the rate-limiting enzyme of the de novo pyrimidine production pathway, is essential in the production of RNA and DNA and is overexpressed in malignancies such as AML, skin cancer, breast cancer, and lung cancer, thereby highlighting DHODH as a viable target for developing drugs to combat lung cancer. Herein, rational drug design and computational techniques were used to discover novel DHODH inhibitors. A small combinatorial library was generated, and the top hits were synthesized and tested for anticancer activity against three lung cancer cell lines. Among the tested compounds, compound 5c possessed a stronger cytotoxicity (TC50 of 11 μM) compared to the standard FDA-approved drug (Regorafenib, TC50 of 13 μM) on the A549 cell line. Furthermore, compound 5c demonstrated potent inhibitory activity against hDHODH at a nanomolar level of 421 nM. DFT, molecular docking, molecular dynamic simulations, and free energy calculations were also carried out to understand the inhibitory mechanisms of the synthesized scaffolds. These in silico studies identified key mechanisms and structural features that will be crucial for future studies.

| S-EPMC10286098 | biostudies-literature

Aggregation-Induced Emissive and Circularly Polarized Homogeneous Sulfono-γ-AApeptide Foldamers.

Project description:Through our continuous effort in developing a new class of foldamers, we have both designed and synthesized homogenous sulfono-γ-AApeptides using tetraphenylethylene (TPE) moieties attached to the backbone as luminogenic sidechains. Based on previous crystal structures, we have found that these foldamers adopted a left-handed 414-helix. Due to the constraint of the helical scaffold, the rotation of the TPE moieties were restricted, leading to fluorescent emissive properties with high quantum yields not only at the aggregate state but also in solution. Investigation of the relationship between the structure and fluorescence behavior reveals that emission was induced by the combined effect of the aggregation-induced emission (AIE) and the rotated restriction from the backbone. Furthermore, as the packing mode of the luminogens could be precisely adjusted by the helical backbone, these foldamers were found to be circularly polarizable with relatively large luminescence dissymmetry factor (glum). Interestingly, possessing cationic amphipathic structures similar to that of host-defense peptides (HDPs), these sulfono-γ-AApeptides were able to inhibit the growth of Gram-positive bacteria methicillin-resistant S. aureus (MRSA) through membrane interactions.

| S-EPMC7567131 | biostudies-literature

Rational Design and Synthesis of Right-Handed d-Sulfono-γ-AApeptide Helical Foldamers as Potent Inhibitors of Protein-Protein Interactions.

Project description:Novel unprecedented helical foldamers have been effectively designed and synthesized. The homogeneous right-handed d-sulfono-γ-AApeptides represent a new generation of unnatural helical peptidomimetics, which have similar folding conformation to α-peptides, making them an ideal molecular scaffold to design α-helical mimetics. As demonstrated with p53-MDM2 PPI as a model application, the right-handed d-sulfono-γ-AApeptides reveal much-enhanced binding affinity compared to the p53 peptide. The design of d-sulfono-γ-AApeptides may provide a new and alternative strategy to modulate protein-protein interactions.

| S-EPMC8204676 | biostudies-literature

Identification of candidate IgG biomarkers for Alzheimer's disease via combinatorial library screening.

Project description:The adaptive immune system is thought to be a rich source of protein biomarkers, but diagnostically useful antibodies remain unknown for a large number of diseases. This is, in part, because the antigens that trigger an immune response in many diseases remain unknown. We present here a general and unbiased approach to the identification of diagnostically useful antibodies that avoids the requirement for antigen identification. This method involves the comparative screening of combinatorial libraries of unnatural, synthetic molecules against serum samples obtained from cases and controls. Molecules that retain far more IgG antibodies from the case samples than the controls are identified and subsequently tested as capture agents for diagnostically useful antibodies. The utility of this method is demonstrated using a mouse model for multiple sclerosis and via the identification of two candidate IgG biomarkers for Alzheimer's disease.

| S-EPMC3066439 | biostudies-literature

The activity of sulfono-γ-AApeptide helical foldamers that mimic GLP-1.

Project description:Existing long α-helix mimicking necessitates the retention of most natural amino acid residues to maintain their biological activity. Here, we report the exploration of helical sulfono-γ-AApeptides with entire unnatural backbones for their ability to structurally and functionally mimic glucagon-like peptide 1 (GLP-1). Our findings suggest that efficient construction of novel GLP-1 receptor (GLP-1R) agonists could be achieved with nanomolar potencies. In addition, the resulting sulfono-γ-AApeptides were also proved to display remarkable stability against enzymatic degradation compared to GLP-1, augmenting their biological potential. This alternative strategy of α-helix mimicking, as a proof of concept, could provide a new paradigm to prepare GLP-1R agonists.

| S-EPMC7228743 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data