Detecting nitrile-containing small molecules by infrared photothermal microscopy

The Analyst ◽  
2021 ◽  
Vol 146 (7) ◽  
pp. 2307-2312
Author(s):  
Fangfang Tai ◽  
Kota Koike ◽  
Hiroyuki Kawagoe ◽  
Jun Ando ◽  
Yasuaki Kumamoto ◽  
...  
Keyword(s):  
Small Molecules ◽  
Nitrile Group ◽  
Carbonyl Cyanide ◽  
Target Molecules ◽  
Photothermal Microscopy ◽  
Photothermal Imaging ◽  
In Cells

We demonstrated IR photothermal imaging of trifluoromethoxy carbonyl cyanide phenylhydrazone (FCCP) in cells. The result indicates that a nitrile group can be used as a vibrational tag to image target molecules.

scholarly journals Fluorogenic Aptasensors with Small Molecules

Chemosensors ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 54
Author(s):  
Eun-Song Lee ◽  
Jeong Min Lee ◽  
Hea-Jin Kim ◽  
Young-Pil Kim
Keyword(s):  
Small Molecules ◽  
In Vitro Selection ◽  
Molecular Beacon ◽  
Future Directions ◽  
Rna Molecules ◽  
Amplification Process ◽  
Target Molecules ◽  
And Performance ◽  
Fluorescence Turn On

Aptamers are single-stranded DNA or RNA molecules that can be identified through an iterative in vitro selection–amplification process. Among them, fluorogenic aptamers in response to small molecules have been of great interest in biosensing and bioimaging due to their rapid fluorescence turn-on signals with high target specificity and low background noise. In this review, we report recent advances in fluorogenic aptasensors and their applications to in vitro diagnosis and cellular imaging. These aptasensors modulated by small molecules have been implemented in different modalities that include duplex or molecular beacon-type aptasensors, aptazymes, and fluorogen-activating aptamer reporters. We highlight the working principles, target molecules, modifications, and performance characteristics of fluorogenic aptasensors, and discuss their potential roles in the field of biosensor and bioimaging with future directions and challenges.

scholarly journals Inhibition of Non-ATG Translational Events in Cells via Covalent Small Molecules Targeting RNA

2015 ◽  
Vol 137 (16) ◽  
pp. 5336-5345 ◽  
Author(s):  
Wang-Yong Yang ◽  
Henry D. Wilson ◽  
Sai Pradeep Velagapudi ◽  
Matthew D. Disney
Keyword(s):  
Small Molecules ◽  
In Cells

scholarly journals Small Gold Nanorods with Tunable Absorption for Photothermal Microscopy in Cells

2016 ◽  
Vol 4 (2) ◽  
pp. 1600280 ◽  
Author(s):  
Edakkattuparambil Sidharth Shibu ◽  
Nadezda Varkentina ◽  
Laurent Cognet ◽  
Brahim Lounis
Keyword(s):  
Gold Nanorods ◽  
Photothermal Microscopy ◽  
Tunable Absorption ◽  
In Cells

scholarly journals Screening of a Focused Ubiquitin-Proteasome Pathway Inhibitor Library Identifies Small Molecules as Novel Modulators of Botulinum Neurotoxin Type A Toxicity

2021 ◽  
Vol 12 ◽  
Author(s):  
Edanur Sen ◽  
Krishna P. Kota ◽  
Rekha G. Panchal ◽  
Sina Bavari ◽  
Erkan Kiris
Keyword(s):  
Small Molecules ◽  
Ubiquitin Proteasome Pathway ◽  
Lead Compounds ◽  
Botulinum Neurotoxins ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
The Stability ◽  
Dose Dependent ◽  
In Cells

Botulinum neurotoxins (BoNTs) are known as the most potent bacterial toxins, which can cause potentially deadly disease botulism. BoNT Serotype A (BoNT/A) is the most studied serotype as it is responsible for most human botulism cases, and its formulations are extensively utilized in clinics for therapeutic and cosmetic applications. BoNT/A has the longest-lasting effect in neurons compared to other serotypes, and there has been high interest in understanding how BoNT/A manages to escape protein degradation machinery in neurons for months. Recent work demonstrated that an E3 ligase, HECTD2, leads to efficient ubiquitination of the BoNT/A Light Chain (A/LC); however, the dominant activity of a deubiquitinase (DUB), VCIP135, inhibits the degradation of the enzymatic component. Another DUB, USP9X, was also identified as a potential indirect contributor to A/LC degradation. In this study, we screened a focused ubiquitin-proteasome pathway inhibitor library, including VCIP135 and USP9X inhibitors, and identified ten potential lead compounds affecting BoNT/A mediated SNAP-25 cleavage in neurons in pre-intoxication conditions. We then tested the dose-dependent effects of the compounds and their potential toxic effects in cells. A subset of the lead compounds demonstrated efficacy on the stability and ubiquitination of A/LC in cells. Three of the compounds, WP1130 (degrasyn), PR-619, and Celastrol, further demonstrated efficacy against BoNT/A holotoxin in an in vitro post-intoxication model. Excitingly, PR-619 and WP1130 are known inhibitors of VCIP135 and USP9X, respectively. Modulation of BoNT turnover in cells by small molecules can potentially lead to the development of effective countermeasures against botulism.

scholarly journals Lifespan-increasing drug nordihydroguaiaretic acid inhibits p300 and activates autophagy

2019 ◽  
Author(s):  
Tugsan Tezil ◽  
Manish Chamoli ◽  
Che-Ping Ng ◽  
Roman P. Simon ◽  
Victoria J. Butler ◽  
...  
Keyword(s):  
Small Molecules ◽  
Physiological Function ◽  
Nordihydroguaiaretic Acid ◽  
Mechanistic Insight ◽  
Epigenetic Regulator ◽  
Novel Target ◽  
Cellular Thermal Shift Assay ◽  
Insight Into ◽  
In Cells

AbstractAging is characterized by the progressive loss of physiological function in all organisms. Remarkably, the aging process can be modulated by environmental modifications, including diet and small molecules. The natural compound nordihydroguaiaretic acid (NDGA) robustly increases lifespan in flies and mice, but its mechanism of action remains unclear. Here, we report that NDGA is an inhibitor of the epigenetic regulator p300. We find that NDGA inhibits p300 acetyltransferase activity in vitro and suppresses acetylation of a key p300 target in histones (i.e., H3K27) in cells. We use the cellular thermal shift assay to uniquely demonstrate NDGA binding to p300 in cells. Finally, in agreement with recent findings indicating that p300 is a potent blocker of autophagy, we show that NDGA treatment induces autophagy. These findings identify p300 as a novel target of NDGA and provide mechanistic insight into its role in longevity.

scholarly journals Epistatic mutations in PUMA BH3 drive an alternate binding mode to potently and selectively inhibit anti-apoptotic Bfl-1

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Justin M Jenson ◽  
Jeremy A Ryan ◽  
Robert A Grant ◽  
Anthony Letai ◽  
Amy E Keating
Keyword(s):  
Small Molecules ◽  
Cancer Progression ◽  
Binding Mode ◽  
Mitochondrial Outer Membrane ◽  
Binding Partners ◽  
Peptide Binding Groove ◽  
Cell Permeable Peptide ◽  
Binding Groove ◽  
Resistance To Chemotherapy ◽  
In Cells

Overexpression of anti-apoptotic Bcl-2 family proteins contributes to cancer progression and confers resistance to chemotherapy. Small molecules that target Bcl-2 are used in the clinic to treat leukemia, but tight and selective inhibitors are not available for Bcl-2 paralog Bfl-1. Guided by computational analysis, we designed variants of the native BH3 motif PUMA that are > 150-fold selective for Bfl-1 binding. The designed peptides potently trigger disruption of the mitochondrial outer membrane in cells dependent on Bfl-1, but not in cells dependent on other anti-apoptotic homologs. High-resolution crystal structures show that designed peptide FS2 binds Bfl-1 in a shifted geometry, relative to PUMA and other binding partners, due to a set of epistatic mutations. FS2 modified with an electrophile reacts with a cysteine near the peptide-binding groove to augment specificity. Designed Bfl-1 binders provide reagents for cellular profiling and leads for developing enhanced and cell-permeable peptide or small-molecule inhibitors.

scholarly journals Targeting Drug Delivery in the Elderly: Are Nanoparticles an Option for Treating Osteoporosis?

2021 ◽  
Vol 22 (16) ◽  
pp. 8932
Author(s):  
Gudrun C. Thurner ◽  
Johannes Haybaeck ◽  
Paul Debbage
Keyword(s):  
Bone Resorption ◽  
Small Molecules ◽  
Living Organism ◽  
The Elderly ◽  
Therapeutic Agents ◽  
Common Disease ◽  
Practical Application ◽  
Targeted Nanoparticles ◽  
Target Molecules ◽  
Tissue Compartments

Nanoparticles bearing specific targeting groups can, in principle, accumulate exclusively at lesion sites bearing target molecules, and release therapeutic agents there. However, practical application of targeted nanoparticles in the living organism presents challenges. In particular, intravasally applied nanoparticles encounter physical and physiological barriers located in blood vessel walls, blocking passage from the blood into tissue compartments. Whereas small molecules can pass out of the blood, nanoparticles are too large and need to utilize physiological carriers enabling passage across endothelial walls. The issues associated with crossing blood-tissue barriers have limited the usefulness of nanoparticles in clinical applications. However, nanoparticles do not encounter blood-tissue barriers if their targets are directly accessible from the blood. This review focuses on osteoporosis, a disabling and common disease for which therapeutic strategies are limited. The target sites for therapeutic agents in osteoporosis are located in bone resorption pits, and these are in immediate contact with the blood. There are specific targetable biomarkers within bone resorption pits. These present nanomedicine with the opportunity to treat a major disease by use of simple nanoparticles loaded with any of several available effective therapeutics that, at present, cannot be used due to their associated side effects.

scholarly journals Hunting Molecules in Complex Matrices with SPME Arrows: A Review

Separations ◽  
2020 ◽  
Vol 7 (1) ◽  
pp. 12 ◽  
Author(s):  
Jason S. Herrington ◽  
German A. Gómez-Ríos ◽  
Colton Myers ◽  
Gary Stidsen ◽  
David S. Bell
Keyword(s):  
Small Molecules ◽  
Solid Phase Microextraction ◽  
Solid Phase ◽  
Forensic Analysis ◽  
Public Disclosure ◽  
Complex Matrices ◽  
Coating Materials ◽  
Recent Developments ◽  
Target Molecules ◽  
Operational Aspects

Thirty years since the invention and public disclosure of solid phase microextraction (SPME), the technology continues evolving and inspiring several other green extraction technologies amenable for the collection of small molecules present in complex matrices. In this manuscript, we review the fundamental and operational aspects of a novel SPME geometry that can be used to “hunt” target molecules in complex matrices: the SPME Arrow. In addition, a series of applications in environmental, food, cannabis and forensic analysis are succinctly covered. Finally, special emphasis is placed on novel interfaces to analytical instrumentation, as well as recent developments in coating materials for the SPME Arrow.

Expedited Mapping of the Ligandable Proteome Using Fully Functionalized Enantiomeric Probe Pairs

2019 ◽  
Author(s):  
Benjamin Cravatt ◽  
Yujia Wang ◽  
melissa dix ◽  
jarrett remsberg ◽  
hsin-yu lee ◽  
...  
Keyword(s):  
Small Molecules ◽  
Protein Interactions ◽  
Binding Potential ◽  
Protein Fragment ◽  
Chemical Proteomics ◽  
Functional Sites ◽  
Structure Activity ◽  
Ligand Discovery ◽  
Absolute Stereochemistry ◽  
In Cells

<div>A fundamental challenge in chemical biology and medicine is to understand and expand the fraction of the human proteome that can be targeted by small molecules. We recently described a strategy that integrates fragment-based ligand discovery with chemical proteomics to furnish global portraits of reversible small molecule-protein interactions in human cells.</div><div>Excavating clear structure-activity relationships from these “ligandability” maps, however, was confounded by the distinct physicochemical properties and corresponding overall protein-binding potential of individual fragments. Here, we describe a compelling solution to this problem by introducing a next-generation set of fully functionalized fragments (FFFs) differing only in absolute stereochemistry. Using these enantiomeric probe pairs, or “enantioprobes”, we identify numerous stereoselective protein-fragment interactions in cells and show that these interactions occur at functional sites on proteins from diverse classes. Our findings thus indicate that incorporating chirality into FFF libraries provides a robust and streamlined method to discover ligandable proteins in cells.</div>

scholarly journals Translation of the intrinsically disordered protein α-synuclein is inhibited by a small molecule targeting its structured mRNA

2020 ◽  
Vol 117 (3) ◽  
pp. 1457-1467 ◽  
Author(s):  
Peiyuan Zhang ◽  
Hye-Jin Park ◽  
Jie Zhang ◽  
Eunsung Junn ◽  
Ryan J. Andrews ◽  
...  
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
Intrinsically Disordered Proteins ◽  
Lewy Bodies ◽  
Disordered Proteins ◽  
Lewy Neurites ◽  
Protein Levels ◽  
Intrinsically Disordered ◽  
In Cells

Many proteins are refractory to targeting because they lack small-molecule binding pockets. An alternative to drugging these proteins directly is to target the messenger (m)RNA that encodes them, thereby reducing protein levels. We describe such an approach for the difficult-to-target protein α-synuclein encoded by the SNCA gene. Multiplication of the SNCA gene locus causes dominantly inherited Parkinson’s disease (PD), and α-synuclein protein aggregates in Lewy bodies and Lewy neurites in sporadic PD. Thus, reducing the expression of α-synuclein protein is expected to have therapeutic value. Fortuitously, the SNCA mRNA has a structured iron-responsive element (IRE) in its 5′ untranslated region (5′ UTR) that controls its translation. Using sequence-based design, we discovered small molecules that target the IRE structure and inhibit SNCA translation in cells, the most potent of which is named Synucleozid. Both in vitro and cellular profiling studies showed Synucleozid directly targets the α-synuclein mRNA 5′ UTR at the designed site. Mechanistic studies revealed that Synucleozid reduces α-synuclein protein levels by decreasing the amount of SNCA mRNA loaded into polysomes, mechanistically providing a cytoprotective effect in cells. Proteome- and transcriptome-wide studies showed that the compound’s selectivity makes Synucleozid suitable for further development. Importantly, transcriptome-wide analysis of mRNAs that encode intrinsically disordered proteins revealed that each has structured regions that could be targeted with small molecules. These findings demonstrate the potential for targeting undruggable proteins at the level of their coding mRNAs. This approach, as applied to SNCA, is a promising disease-modifying therapeutic strategy for PD and other α-synucleinopathies.

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