Browse
Submit Data
Databases
API
Help

Dataset Information

15 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

A Platform for the Detection of Trypanosomes via Selective Small Molecule Recognition.

ABSTRACT: Trypanothione (TSH2), a metabolite unique to trypanosomal parasites, was evaluated as a potential biomarker for trypanosomal infection using fluorescence as the means of detection. Fluoroescein arsenical helix binder (FLASH) was prepared and used to detect TSH2. Since it has low background fluorescence and forms a highly emissive complex with TSH2, it can be used to detect low micromolar concentrations of TSH2 in serum. The large dynamic range of FLASH and its selectivity for detection of the dithiol metabolite indicate that arsenical probes may offer a promising new platform for the diagnosis of trypanosomal infection.

SUBMITTER: Beaulieu ED

PROVIDER: S-EPMC4018164 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

A Platform for the Detection of Trypanosomes via Selective Small Molecule Recognition.

Beaulieu Ellen D ED Olson Lori L LL Tanga Mary J MJ

ACS medicinal chemistry letters 20110418 7

Trypanothione (TSH2), a metabolite unique to trypanosomal parasites, was evaluated as a potential biomarker for trypanosomal infection using fluorescence as the means of detection. Fluoroescein arsenical helix binder (FLASH) was prepared and used to detect TSH2. Since it has low background fluorescence and forms a highly emissive complex with TSH2, it can be used to detect low micromolar concentrations of TSH2 in serum. The large dynamic range of FLASH and its selectivity for detection of the di ...[more]

PMID: 24900348

Similar Datasets

Selective Small Molecule Recognition of RNA Base Pairs.

Project description:Many types of RNAs exist in the human transcriptome, yet only the bacterial ribosome has been exploited as a small molecule drug target. Aside from rRNA, other cellular RNAs such as noncoding RNAs have primarily secondary structure and limited tertiary structure. Within these secondary structures of noncanonically paired and unpaired regions, more than 50% are base paired, with most efforts to target these structures focused on looped regions. A void exists in the availability of small molecules capable of targeting RNA base pairs. Using chemoinformatics, an RNA-focused library enriched for nitrogen-containing heterocycles was developed and tested for binding RNA base pairs, leading to the identification of six selective and previously unknown binders. While all binders were derivatives of benzimidazoles, those with expanded aromatic polycycles bound selectively to AU pairs, while those with flexible urea side chains bound selectively to GC pairs. Two of the three selective GC pair binders can distinguish between two different orientations, 5'GG/3'CC and 5'GC/3'CG pairs. Furthermore, all six molecules showed >50-fold selectivity for RNA over DNA. These studies provide foundational knowledge to better exploit RNA as targets for small molecule chemical probes or lead therapeutics by using modules that target RNA base pairs.

| S-EPMC6325646 | biostudies-literature

Small molecule recognition of c-Src via the Imatinib-binding conformation.

Project description:The cancer drug, Imatinib, is a selective Abl kinase inhibitor that does not inhibit the closely related kinase c-Src. This one drug and its ability to selectively inhibit Abl over c-Src has been a guiding principle in virtually all kinase drug discovery efforts in the last 15 years. A prominent hypothesis explaining the selectivity of Imatinib is that Abl has an intrinsic ability to adopt an inactive conformation (termed DFG-out), whereas c-Src appears to pay a high intrinsic energetic penalty for adopting this conformation, effectively excluding Imatinib from its ATP pocket. This explanation of the difference in binding affinity of Imatinib for Abl versus c-Src makes the striking prediction that it would not be possible to design an inhibitor that binds to the DFG-out conformation of c-Src with high affinity. We report the discovery of a series of such inhibitors. We use structure-activity relationships and X-ray crystallography to confirm our findings. These studies suggest that small molecules are capable of inducing the generally unfavorable DFG-out conformation in c-Src. Structural comparison between c-Src in complex with these inhibitors allows us to speculate on the differential selectivity of Imatinib for c-Src and Abl.

| S-EPMC2702663 | biostudies-literature

Selective Recognition of a Single HIV-1 G-Quadruplex by Ultrafast Small-Molecule Screening.

Project description:G-quadruplexes (G4s) are implicated in pathological processes such as cancer and infective diseases. Their targeting with G4-ligands has shown therapeutic capacity. Most of the current G4-ligands are planar molecules, do not discriminate among G4s, and have poor druglike properties. The available methods to identify compounds selective for one single G4 are often time-consuming. Here, we describe the development, validation, and application of an affinity-selection mass spectrometry method that employs unlabeled G4 oligonucleotides as targets and allows testing of up to 320 unmodified small molecules in a single tube. As a proof of concept, this method was applied to screen a library of 40 000 druglike molecules against two G4s, transcriptional regulators of the HIV-1 LTR promoter. We identified nonplanar pyrazolopyrimidines that selectively recognize and stabilize the major HIV-1 LTR G4 possibly by fitting and binding through H-bonding in its unique binding pocket. The compounds inhibit LTR promoter activity and HIV-1 replication. We propose this method to prompt the fast development of new G4-based therapeutics.

| S-EPMC8613737 | biostudies-literature

Simultaneous detection of small molecule thiols with a simple <sup>19</sup>F NMR platform.

Project description:Thiols play critical roles in regulating biological functions and have wide applications in pharmaceutical and biomedical industries. However, we still lack a general approach for the simultaneous detection of various thiols, especially in complex systems. Herein, we establish a 19F NMR platform where thiols are selectively fused into a novelly designed fluorinated receptor that has two sets of environmentally different 19F atoms with fast kinetics (k 2 = 0.73 mM-1 min-1), allowing us to generate unique two-dimensional codes for about 20 thiols. We demonstrate the feasibility of the approach by reliably quantifying thiol drug content in tablets, discriminating thiols in living cells, and for the first time monitoring the thiol related metabolism pathway at the atomic level. Moreover, the method can be easily extended to detect the activity of thiol related enzymes such as γ-glutamyl transpeptidase. We envision that the versatile platform will be a useful tool for detecting thiols and elucidating thiol-related processes in complex systems.

| S-EPMC8179020 | biostudies-literature

Small molecule detection with aptamer based lateral flow assays: Applying aptamer-C-reactive protein cross-recognition for ampicillin detection.

Project description:Aptamer-based lateral flow assays (LFAs) are an emerging field of aptamer applications due to numerous potential applications. When compared to antibodies, potential advantages like cost effectiveness or lower batch to batch variations are evident. The development of LFAs for small molecules, however, is still challenging due to several reasons, primarily linked to target size and accessible interaction sites. In small molecule analysis, however, aptamers in many cases are preferable since immunogenicity is not required and they may exhibit even higher target selectivity. We report the first cross-recognition of a small molecule (ampicillin) and a protein (C-reactive protein), predicted by in-silico analysis, then experimentally confirmed - using two different aptamers. These features can be exploited for developing an aptamer-based LFA for label-free ampicillin detection, functioning also for analysis in milk extract. Most importantly, the principal setup denotes a novel, transferable and versatile general approach for detection of small molecules using competitive LFAs, unlikely to be generally realized by aptamer-DNA-binding otherwise.

| S-EPMC5884802 | biostudies-other

An in vivo multiplexed small-molecule screening platform.

Project description:Phenotype-based small-molecule screening is a powerful method to identify molecules that regulate cellular functions. However, such screens are generally performed in vitro under conditions that do not necessarily model complex physiological conditions or disease states. Here, we use molecular cell barcoding to enable direct in vivo phenotypic screening of small-molecule libraries. The multiplexed nature of this approach allows rapid in vivo analysis of hundreds to thousands of compounds. Using this platform, we screened >700 covalent inhibitors directed toward hydrolases for their effect on pancreatic cancer metastatic seeding. We identified multiple hits and confirmed the relevant target of one compound as the lipase ABHD6. Pharmacological and genetic studies confirmed the role of this enzyme as a regulator of metastatic fitness. Our results highlight the applicability of this multiplexed screening platform for investigating complex processes in vivo.

| S-EPMC5088491 | biostudies-literature

Blank peak current-suppressed electrochemical aptameric sensing platform for highly sensitive signal-on detection of small molecule.

Project description:In this contribution, an electrochemical aptameric sensing scheme for the sensitive detection of small molecules is proposed using adenosine as a target model. A ferrocene (Fc)-functionalized thiolated aptamer probe is adapted and immobilized onto an electrode surface. Introducing a recognition site for EcoRI into the aptamer sequence not only suppresses the peak current corresponding to blank sample but also provides a signal-on response mechanism. In the absence of adenosine, the aptamer can fold into a hairpin structure and form a cleavable double-stranded region. Fc is capable of being removed from electrode surface by treatment with endonuclease, and almost no peak current is observed. The adenosine/aptamer binding induces the conformational transition of designed aptamer, dissociating the cleavable double-stranded segment. Therefore, the integrated aptamer sequence is maintained when exposing to endonuclease, generating a peak current of Fc. Utilizing the present sensing scheme, adenosine even at a low concentration can give a detectable current signal. Thus, a detection limit of 10(-10) M and a linear response range from 3.74×10(-9) to 3.74×10(-5)?M are achieved. The proposed proof-of-principle of a novel electrochemical sensing is expected to extend to establish various aptameric platforms for the analysis of a broad range of target molecules of interest.

| S-EPMC2978380 | biostudies-literature

Identification of a small-molecule ligand of the epigenetic reader protein Spindlin1 via a versatile screening platform.

Project description:Epigenetic modifications of histone tails play an essential role in the regulation of eukaryotic transcription. Writer and eraser enzymes establish and maintain the epigenetic code by creating or removing posttranslational marks. Specific binding proteins, called readers, recognize the modifications and mediate epigenetic signalling. Here, we present a versatile assay platform for the investigation of the interaction between methyl lysine readers and their ligands. This can be utilized for the screening of small-molecule inhibitors of such protein-protein interactions and the detailed characterization of the inhibition. Our platform is constructed in a modular way consisting of orthogonal in vitro binding assays for ligand screening and verification of initial hits and biophysical, label-free techniques for further kinetic characterization of confirmed ligands. A stability assay for the investigation of target engagement in a cellular context complements the platform. We applied the complete evaluation chain to the Tudor domain containing protein Spindlin1 and established the in vitro test systems for the double Tudor domain of the histone demethylase JMJD2C. We finally conducted an exploratory screen for inhibitors of the interaction between Spindlin1 and H3K4me3 and identified A366 as the first nanomolar small-molecule ligand of a Tudor domain containing methyl lysine reader.

| S-EPMC4872087 | biostudies-other

A novel EMT-selective small molecule induces ER stress

Project description:Carcinoma cells can acquire key malignant traits by reprogramming their differentiation state via an epithelial-to-mesenchymal transition (EMT). Cancer cells that undergo EMT become invasive and resist a wide range of therapies including most chemotherapy drugs and radiation. Such cells are also able to efficiently seed primary and metastatic tumors, making them functionally indistinguishable from tumor-initiating or cancer stem-like cells (TICs or CSCs). Therefore, there is significant interest in finding vulnerabilities of cancer cells that have undergone EMT. A potent EMT-selective small molecule was discovered through a large-scale chemical screen. We used microarray analysis to understand the biological effects of this compound. HMLE_ctrl (human MECs, infected with a pBabe-shGFP retrovirus) and HMLE_Twist (human MECs, infected with a pBabe-Twist retrovirus) cells were treated with solvent control (DMSO), 5 ÂµM or 10 ÂµM of Cmp302 for 6 hours. Microarray analysis was performed to profile global gene expression.

2014-04-09 | E-GEOD-55604 | biostudies-arrayexpress

Aptamer Recognition of Multiplexed Small-Molecule-Functionalized Substrates.

Project description:Aptamers are chemically synthesized oligonucleotides or peptides with molecular recognition capabilities. We investigated recognition of substrate-tethered small-molecule targets, using neurotransmitters as examples, and fluorescently labeled DNA aptamers. Substrate regions patterned via microfluidic channels with dopamine or ??l-tryptophan were selectively recognized by previously identified dopamine or l-tryptophan aptamers, respectively. The on-substrate dissociation constant determined for the dopamine aptamer was comparable to, though, slightly greater than the previously determined solution dissociation constant. Using prefunctionalized neurotransmitter-conjugated oligo(ethylene glycol) alkanethiols and microfluidics patterning, we produced multiplexed substrates to capture and to sort aptamers. Substrates patterned with l-3,4-dihydroxyphenylalanine, l- threo-dihydroxyphenylserine, and l-5-hydroxytryptophan enabled comparison of the selectivity of the dopamine aptamer for different targets via simultaneous determination of in situ binding constants. Thus, beyond our previous demonstrations of recognition by protein binding partners (i.e., antibodies and G-protein-coupled receptors), strategically optimized small-molecule-functionalized substrates show selective recognition of nucleic acid binding partners. These substrates are useful for side-by-side target comparisons and future identification and characterization of novel aptamers targeting neurotransmitters or other important small molecules.

| S-EPMC6087467 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

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