Browse
Submit Data
Databases
API
Help

Dataset Information

15 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Small-Molecule Inhibitors of the NusB-NusE Protein-Protein Interaction with Antibiotic Activity.

ABSTRACT: The NusB-NusE protein-protein interaction (PPI) is critical to the formation of stable antitermination complexes required for stable RNA transcription in all bacteria. This PPI is an emerging antibacterial drug target. Pharmacophore-based screening of the mini-Maybridge compound library (56 000 molecules) identified N,N'-[1,4-butanediylbis(oxy-4,1-phenylene)]bis(N-ethyl)urea 1 as a lead of interest. Competitive enzyme-linked immunosorbent assay screening validated 1 as a 20 μM potent inhibitor of NusB-NusE. Four focused compound libraries based on 1, comprising 34 compounds in total were designed, synthesized, and evaluated as NusB-NusE PPI inhibitors. Ten analogues displayed NusB-NusE PPI inhibition ≥50% at 25 μM concentration in vitro. In contrast to representative Gram-negative Escherichia coli and Gram-positive Bacillus subtilis species, these analogues showed up to 100% growth inhibition at 200 μM. 2-((Z)-4-(((Z)-4-(4-((E)-(Carbamimidoylimino)methyl)phenoxy)but-2-en-1-yl)oxy)benzylidene)hydrazine-1-carboximidamide 22 showed excellent activity against important pathogens. With minimum inhibitory concentration values of ≤3 μg/mL for Gram-positive Streptococcus pneumoniae and methicillin-resistant Staphylococcus aureus and ≤51 μg/mL for Gram-negative Pseudomonas aeruginosa and Acinetobacter baumannii, 22 is a potent lead for a novel antibacterial target. Epifluorescence studies in live bacteria were consistent with 22, inhibiting the NusB-NusE PPI as proposed.

SUBMITTER: Cossar PJ

PROVIDER: S-EPMC6044933 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Shared Molecules

Only show the datasets with similarity scores above: 0.5

Threshold

0.5

Similar Datasets

Small molecule inhibitors of trans-translation have broad-spectrum antibiotic activity.

Project description:The trans-translation pathway for protein tagging and ribosome release plays a critical role for viability and virulence in a wide range of pathogens but is not found in animals. To explore the use of trans-translation as a target for antibiotic development, a high-throughput screen and secondary screening assays were used to identify small molecule inhibitors of the pathway. Compounds that inhibited protein tagging and proteolysis of tagged proteins were recovered from the screen. One of the most active compounds, KKL-35, inhibited the trans-translation tagging reaction with an IC50 = 0.9 µM. KKL-35 and other compounds identified in the screen exhibited broad-spectrum antibiotic activity, validating trans-translation as a target for drug development. This unique target could play a key role in combating strains of pathogenic bacteria that are resistant to existing antibiotics.

| S-EPMC3690859 | biostudies-other

Structure-activity relationship study of 4EGI-1, small molecule eIF4E/eIF4G protein-protein interaction inhibitors.

Project description:Protein-protein interactions are critical for regulating the activity of translation initiation factors and multitude of other cellular process, and form the largest block of untapped albeit most challenging targets for drug development. 4EGI-1, (E/Z)-2-(2-(4-(3,4-dichlorophenyl)thiazol-2-yl)hydrazono)-3-(2-nitrophenyl)propanoic acid, is a hit compound discovered in a screening campaign of small molecule libraries as an inhibitor of translation initiation factors eIF4E and eIF4G protein-protein interaction; it inhibits translation initiation in vitro and in vivo. A series of 4EGI-1-derived thiazol-2-yl hydrazones have been designed and synthesized in order to delineate the structural latitude and improve its binding affinity to eIF4E, and increase its potency in inhibiting the eIF4E/eIF4G interaction. Probing a wide range of substituents on both phenyl rings comprising the 3-phenylpropionic acid and 4-phenylthiazolidine moieties in the context of both E- and Z-isomers of 4EGI-1 led to analogs with enhanced binding affinity and translation initiation inhibitory activities.

| S-EPMC4128255 | biostudies-literature

Identification of small-molecule protein-protein interaction inhibitors for NKG2D.

Project description:NKG2D (natural-killer group 2, member D) is a homodimeric transmembrane receptor that plays an important role in NK, γδ+, and CD8+ T cell-mediated immune responses to environmental stressors such as viral or bacterial infections and oxidative stress. However, aberrant NKG2D signaling has also been associated with chronic inflammatory and autoimmune diseases, and as such NKG2D is thought to be an attractive target for immune intervention. Here, we describe a comprehensive small-molecule hit identification strategy and two distinct series of protein-protein interaction inhibitors of NKG2D. Although the hits are chemically distinct, they share a unique allosteric mechanism of disrupting ligand binding by accessing a cryptic pocket and causing the two monomers of the NKG2D dimer to open apart and twist relative to one another. Leveraging a suite of biochemical and cell-based assays coupled with structure-based drug design, we established tractable structure-activity relationships with one of the chemical series and successfully improved both the potency and physicochemical properties. Together, we demonstrate that it is possible, albeit challenging, to disrupt the interaction between NKG2D and multiple protein ligands with a single molecule through allosteric modulation of the NKG2D receptor dimer/ligand interface.

| S-EPMC10160951 | biostudies-literature

Recent Small-Molecule Inhibitors of the p53-MDM2 Protein-Protein Interaction.

Project description:This review presents the last decade of studies on the synthesis of various types of small-molecule inhibitors of the p53- Mouse double minute 2 homolog (MDM2) protein-protein interaction. The main focus is placed on synthetic approaches to such molecules, their cytotoxicity, and MDM2 binding characteristics.

| S-EPMC7179467 | biostudies-literature

Small-Molecule Inhibitors of the CD40-CD40L Costimulatory Protein-Protein Interaction.

Project description:Costimulatory interactions are required for T cell activation and development of an effective immune response; hence, they are valuable therapeutic targets for immunomodulation. However, they, as all other protein-protein interactions, are difficult to target by small molecules. Here, we report the identification of novel small-molecule inhibitors of the CD40-CD40L interaction designed starting from the chemical space of organic dyes. For the most promising compounds such as DRI-C21045, activity (IC50) in the low micromolar range has been confirmed in cell assays including inhibition of CD40L-induced activation in NF-κB sensor cells, THP-1 myeloid cells, and primary human B cells as well as in murine allogeneic skin transplant and alloantigen-induced T cell expansion in draining lymph node experiments. Specificity versus other TNF-superfamily interactions (TNF-R1-TNF-α) and lack of cytotoxicity have also been confirmed at these concentrations. These novel compounds provide proof-of-principle evidence for the possibility of small-molecule inhibition of costimulatory protein-protein interactions, establish the structural requirements needed for efficient CD40-CD40L inhibition, and serve to guide the search for such immune therapeutics.

| S-EPMC5823691 | biostudies-literature

AnchorQuery: Rapid online virtual screening for small-molecule protein-protein interaction inhibitors.

Project description:AnchorQuery (http://anchorquery.csb.pitt.edu) is a web application for rational structure-based design of protein-protein interaction (PPI) inhibitors. A specialized variant of pharmacophore search is used to rapidly screen libraries consisting of more than 31 million synthesizable compounds biased by design to preferentially target PPIs. Every library compound is accessible through one-step multi-component reaction (MCR) chemistry and contains an anchor motif that is bioisosteric to an amino acid residue. The inclusion of this anchor not only biases the compounds to interact with proteins, it also enables a rapid, sublinear time pharmacophore search algorithm. AnchorQuery provides all the tools necessary for users to perform online interactive virtual screens of millions of compounds, including pharmacophore elucidation and search, and enrichment analysis. Accessibility: AnchorQuery is freely accessible at http://anchorquery.csb.pitt.edu.

| S-EPMC5734307 | biostudies-literature

High-affinity, small-molecule peptidomimetic inhibitors of MLL1/WDR5 protein-protein interaction.

Project description:Mixed lineage leukemia 1 (MLL1) is a histone H3 lysine 4 (H3K4) methyltransferase, and targeting the MLL1 enzymatic activity has been proposed as a novel therapeutic strategy for the treatment of acute leukemia harboring MLL1 fusion proteins. The MLL1/WDR5 protein-protein interaction is essential for MLL1 enzymatic activity. In the present study, we designed a large number of peptidomimetics to target the MLL1/WDR5 interaction based upon -CO-ARA-NH-, the minimum binding motif derived from MLL1. Our study led to the design of high-affinity peptidomimetics, which bind to WDR5 with K(i) < 1 nM and function as potent antagonists of MLL1 activity in a fully reconstituted in vitro H3K4 methyltransferase assay. Determination of co-crystal structures of two potent peptidomimetics in complex with WDR5 establishes their structural basis for high-affinity binding to WDR5. Evaluation of one such peptidomimetic, MM-102, in bone marrow cells transduced with MLL1-AF9 fusion construct shows that the compound effectively decreases the expression of HoxA9 and Meis-1, two critical MLL1 target genes in MLL1 fusion protein mediated leukemogenesis. MM-102 also specifically inhibits cell growth and induces apoptosis in leukemia cells harboring MLL1 fusion proteins. Our study provides the first proof-of-concept for the design of small-molecule inhibitors of the WDR5/MLL1 protein-protein interaction as a novel therapeutic approach for acute leukemia harboring MLL1 fusion proteins.

| S-EPMC5180416 | biostudies-literature

Small-molecule proteomimetic inhibitors of the HIF-1?-p300 protein-protein interaction.

Project description:The therapeutically relevant hypoxia inducible factor HIF-1?-p300 protein-protein interaction can be orthosterically inhibited with ?-helix mimetics based on an oligoamide scaffold that recapitulates essential features of the C-terminal helix of the HIF-1? C-TAD (C-terminal transactivation domain). Preliminary SAR studies demonstrated the important role of side-chain size and hydrophobicity/hydrophilicity in determining potency. These small molecules represent the first biophysically characterised HIF-1?-p300 PPI inhibitors and the first examples of small-molecule aromatic oligoamide helix mimetics to be shown to have a selective binding profile. Although the compounds were less potent than HIF-1?, the result is still remarkable in that the mimetic reproduces only three residues from the 42-residue HIF-1? C-TAD from which it is derived.

| S-EPMC4159589 | biostudies-literature

Small-molecule inhibitors of the MDM2-p53 protein-protein interaction (MDM2 Inhibitors) in clinical trials for cancer treatment.

Project description:Design of small-molecule inhibitors (MDM2 inhibitors) to block the MDM2-p53 protein-protein interaction has been pursued as a new cancer therapeutic strategy. In recent years, potent, selective, and efficacious MDM2 inhibitors have been successfully obtained and seven such compounds have been advanced into early phase clinical trials for the treatment of human cancers. Here, we review the design, synthesis, properties, preclinical, and clinical studies of these clinical-stage MDM2 inhibitors.

| S-EPMC4329994 | biostudies-literature

Small Molecule Inhibitors of the PCSK9·LDLR Interaction.

Project description:The protein-protein interaction between proprotein convertase subtilisin/kexin type 9 (PCSK9) and low-density lipoprotein receptor (LDLR) is a relatively new, and extremely important, validated therapeutic target for treatment and prevention of heart disease. Experts in the area agree that the first small molecules to disrupt PCSK9·LDLR would represent a milestone in this field, yet few credible leads have been reported. This paper describes how side-chain orientations in preferred conformations of carefully designed chemotypes were compared with LDLR side chains at the PCSK9·LDLR interface to find molecules that would mimic interface regions of LDLR. This approach is an example of the procedure called EKO (Exploring Key Orientations). The guiding hypothesis on which EKO is based is that good matches indicate the chemotypes bearing the same side chains as the protein at the sites of overlay have the potential to disrupt the parent protein-protein interaction. In the event, the EKO procedure and one round of combinatorial fragment-based virtual docking led to the discovery of seven compounds that bound PCSK9 (SPR and ELISA) and had a favorable outcome in a cellular assay (hepatocyte uptake of fluorescently labeled low-density lipoprotein particles) and increased the expression LDLR on hepatocytes in culture. Three promising hit compounds in this series had dissociation constants for PCSK9 binding in the 20-40 μM range, and one of these was modified with a photoaffinity label and shown to form a covalent conjugate with PCSK9 on photolysis.

| S-EPMC6404525 | 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