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Pervasive transcriptome interactions of protein-targeted drugs
Now a reactivity-based RNA profiling strategy can measure the global off-target transcriptome interactions of small-molecule drugs at single-nucleotide resolution. Using this approach, three FDA-approved drugs were evaluated, uncovering pervasive drug–RNA interactions and interactions that perturb RNA functions in cells.
- Linglan Fang
- , Willem A. Velema
- & Eric T. Kool
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Direct mapping of ligandable tyrosines and lysines in cells with chiral sulfonyl fluoride probes
Most chemoproteomic screening approaches are indirect. Now, a chemoproteomic platform based on chiral sulfonyl fluoride probes has been developed for the direct identification of probe-modified tyrosines and lysines in live cells. Stereoselective modification by structurally diverse probes was observed for 634 tyrosines and lysines across functionally diverse protein sites.
- Ying Chen
- , Gregory B. Craven
- & Jack Taunton
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An electroaffinity labelling platform for chemoproteomic-based target identification
The covalent capture of a ligand by its target protein(s) is important for drug-target identification. Now an electrochemically active warhead—diazetidinone—can be leveraged in a chemoproteomics platform for electroaffinity labelling of a ligand’s target protein to afford target-ligand identification in live cells.
- Yu Kawamata
- , Keun Ah Ryu
- & Phil S. Baran
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News & Views |
Warhead assembly in a lethal pathogen
Malleicyprols are highly reactive polyketides responsible for virulence in some pathogenic bacteria. Now, the enzyme that constructs the cyclopropanol warhead of malleicyprols has been identified. This enzyme could represent a useful target for developing new antivirulence therapeutics.
- Elijah Abraham
- & Rebecca A. Butcher
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Article
| Open AccessChemical profiling of DNA G-quadruplex-interacting proteins in live cells
DNA–protein interactions are essential to genome function, but they are challenging to map in a cellular environment. Now, a chemical proteomics approach, which uses DNA G-quadruplex-specific ligands containing a photocrosslinking motif, has enabled the systematic identification of DNA G-quadruplex-binding proteins in live cells.
- Xiaoyun Zhang
- , Jochen Spiegel
- & Shankar Balasubramanian
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Using sulfuramidimidoyl fluorides that undergo sulfur(vi) fluoride exchange for inverse drug discovery
Latent functional groups—typically unreactive unless activated by protein binding—can provide additional selectivity to covalent drugs. Now, compounds containing the weakly electrophilic sulfuramidimidoyl fluoride group, capable of undergoing sulfur(vi) fluoride exchange, have been used to identify reactive proteins in human cell lysate. This approach has identified a compound that conjugates to and inhibits an important anticancer target.
- Gabriel J. Brighty
- , Rachel C. Botham
- & Jeffery W. Kelly
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Repurposing human kinase inhibitors to create an antibiotic active against drug-resistant Staphylococcus aureus, persisters and biofilms
Screening commercial kinase inhibitors for antibacterial activity identified the anticancer drug sorafenib as a major hit. Subsequent structure–activity optimization created a new antibacterial analogue with high potency against methicillin-resistant Staphylococcus aureus, including challenging persisters and biofilms, as well as demonstrating efficacy in an in vivo mouse model. The mode of action involves stimulation of protein secretion and inhibition of menaquinone biosynthesis.
- Philipp Le
- , Elena Kunold
- & Stephan A. Sieber
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Inhibition of human copper trafficking by a small molecule significantly attenuates cancer cell proliferation
Copper is a transition metal ion essential for the regulation of cellular oxidative stress and ATP production. Now, the inhibition of copper-trafficking proteins by a small molecule has been shown to significantly reduce proliferation of cancer cells. The results indicate that copper-trafficking proteins could represent new anti-tumour therapeutic targets.
- Jing Wang
- , Cheng Luo
- & Chuan He
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Revealing the macromolecular targets of complex natural products
Natural products provide a rich source of leads for drug discovery. Now, a computational method is available that can be used to identify the macromolecular targets of these compounds. Much like medicinal chemists' reasoning, the software infers target information by comparing the substructures with those of drugs and other natural products with known targets.
- Daniel Reker
- , Anna M. Perna
- & Gisbert Schneider
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News & Views |
Blocking bacterial defences
Electrochemical sensing of the function of cell-membrane proteins has led to the identification of inhibitors that could provide a new approach to the identification of antimicrobial drugs.
- Ellis C. O'Neill
- & Robert A. Field
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Single-molecule interrogation of a bacterial sugar transporter allows the discovery of an extracellular inhibitor
Capsular polysaccharides (CPS) enclose many pathogenic strains of Escherichia coli, protecting the bacteria from the host. Here, an extracellular blocker of Wza, a pore-forming protein that transports CPS to the cell surface, has been discovered by single-channel electrical recording. Treatment with the blocker exposes the bacterial cell surface and thereby facilitates killing by the human immune system.
- Lingbing Kong
- , Leon Harrington
- & Hagan Bayley