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| Open AccessDiscovery of first-in-class inhibitors of ASH1L histone methyltransferase with anti-leukemic activity
The histone methyltransferase ASH1L plays a role in various diseases, including cancer, and has been validated as a therapeutic target; however, no inhibitors of ASH1L have been reported. Here the authors present small molecule inhibitors of ASH1L and demonstrate their on-target activity in leukemia cells and a mouse model of leukemia.
- David S. Rogawski
- , Jing Deng
- & Jolanta Grembecka
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Article
| Open AccessPhotodegradation of carbon dots cause cytotoxicity
Carbon dots have attracted much attention for biomedical applications but potential degradation and associated toxicity are still poorly understood. Here, the authors report on a study into the photo-degradation of carbon dots, the products produced and associated cytotoxicity.
- Yue-Yue Liu
- , Nan-Yang Yu
- & Ai-Jun Miao
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Article
| Open AccessSmall molecule targeting r(UGGAA)n disrupts RNA foci and alleviates disease phenotype in Drosophila model
Synthetic small molecules modulating RNA structure and function have therapeutic potential for RNA diseases. Here the authors show the mechanism by which a small molecule targets the disease-causing r(UGGAA)n repeat RNAs in spinocerebellar ataxia type 31.
- Tomonori Shibata
- , Konami Nagano
- & Kazuhiko Nakatani
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Article
| Open AccessA therapeutic combination of two small molecule toxin inhibitors provides broad preclinical efficacy against viper snakebite
Snakebite is a life-threatening neglected tropical disease that is currently treated using different antibody-based antivenoms, each effective against bites of specific snake species, but not others. Here, the authors show that a combination of two toxin-inhibiting repurposed drugs provides broad protection in experimental animals against the lethal effects of snakebites from multiple snake species.
- Laura-Oana Albulescu
- , Chunfang Xie
- & Nicholas R. Casewell
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Article
| Open AccessActivation of the IRE1 RNase through remodeling of the kinase front pocket by ATP-competitive ligands
The RNase activity of Inositol-Requiring Enzyme 1 (IRE1) can be allosterically regulated by ATP-competitive inhibitors of the IRE1 kinase domain. Here, the authors identify ATP-competitive IRE1 RNase activators with improved selectivity and cellular activity, and elucidate their mechanism of action.
- Elena Ferri
- , Adrien Le Thomas
- & Weiru Wang
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Article
| Open AccessA dual-labeling probe to track functional mitochondria–lysosome interactions in live cells
Dynamic labeling and tracking of organelle–organelle contacts is essential to understand the formation and function of these interactions. Here the authors present a small molecule probe, Coupa, that labels mitochondria and lysosomes with blue and red fluorescence, respectively.
- Qixin Chen
- , Hongbao Fang
- & Jiajie Diao
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Article
| Open AccessA Cu(II)–ATP complex efficiently catalyses enantioselective Diels–Alder reactions
ATP acts as a co-substrate in enzyme catalysed reactions, but can also specifically bind metal ions. Here, the authors show that ATP interacts with copper ions and forms a Cu(II)-ATP complex that efficiently catalyses Diels-Alder reactions, and determine ATP residues that are essential for this activity.
- Changhao Wang
- , Qianqian Qi
- & Jörg S. Hartig
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Article
| Open AccessPhotoswitchable paclitaxel-based microtubule stabilisers allow optical control over the microtubule cytoskeleton
Light-based modulation of the microtubule (MT) cytoskeleton is an attractive goal for spatiotemporally-resolved MT studies. Here the authors develop a first generation photoswitchable small molecule MT stabiliser based on paclitaxel, allowing optical control over cellular MT dynamics.
- Adrian Müller-Deku
- , Joyce C. M. Meiring
- & Oliver Thorn-Seshold
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Article
| Open AccessInhibitors of BRAF dimers using an allosteric site
FDA-approved RAF inhibitors poorly inhibit BRAF dimers, which limits their clinical efficacy in tumors expressing BRAFV600E mutant monomers. Here the authors identify FDA-approved Ponatinib as an effective inhibitor of BRAF monomers and dimers and designed PHI1, an inhibitor with a unique mode of action and selectivity for oncogenic BRAF dimers.
- Xiomaris M. Cotto-Rios
- , Bogos Agianian
- & Evripidis Gavathiotis
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Article
| Open AccessEnhancing intracellular accumulation and target engagement of PROTACs with reversible covalent chemistry
PROTACs have emerged as promising therapeutic agents but their cellular uptake is often inefficient. Here, the authors show that reversible covalent warhead chemistry improves PROTAC intracellular accumulation and target engagement, and develop a dual inhibitor/degrader of Bruton’s tyrosine kinase
- Wen-Hao Guo
- , Xiaoli Qi
- & Jin Wang
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Article
| Open AccessExploiting natural chemical photosensitivity of anhydrotetracycline and tetracycline for dynamic and setpoint chemo-optogenetic control
Anhydrotetracycline and tetracycline are commonly used chemicals to regulate transcription and translation, respectively. Here the authors exploit the natural photosensitivity of these molecules to place their activity under optical control.
- Armin Baumschlager
- , Marc Rullan
- & Mustafa Khammash
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Article
| Open AccessMechanistic insights into chromatin targeting by leukemic NUP98-PHF23 fusion
Chromosomal NUP98-PHF23 translocation is associated with an aggressive form of AML. Here, the authors report the molecular mechanisms by which NUP98-PHF23 recognizes the histone mark H3K4me3 and provide evidence of a direct link between the association of NUP98-PHD finger chimeras with H3K4me3-rich regions and leukemic transformation.
- Yi Zhang
- , Yiran Guo
- & Tatiana G. Kutateladze
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Article
| Open AccessPotent BRD4 inhibitor suppresses cancer cell-macrophage interaction
Inhibitors of the BET family proteins are limited by their potency and oral bio-availability. Here, the authors report a new BET inhibitor, NHWD-870, with improved potency compared to previous BET inhibitors, and show that it suppresses BRD4 and targets tumour associated macrophages.
- Mingzhu Yin
- , Ying Guo
- & Qin Yan
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Article
| Open AccessDivergent receptor proteins confer responses to different karrikins in two ephemeral weeds
Karrikins are germination stimulants perceived by KAI2 in Arabidopsis. Here the authors show that Brassica tournefortii, a close relative to Arabidopsis, has multiple copies of KAI2 with amino acid substitutions that confer responsiveness to the specific karrikin compounds found in wildfire smoke.
- Yueming Kelly Sun
- , Jiaren Yao
- & Mark T. Waters
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Article
| Open AccessMaltotriose-based probes for fluorescence and photoacoustic imaging of bacterial infections
Sensitive diagnostic tools for bacterial infections of wounds and surgical sites are necessary to enable early detection and determine optimal means of treatment. Here, the authors develop a fluorescent and optoacoustic probe based on a maltotriose scaffold, which is selectively taken up by gram-positive and gram-negative bacteria.
- Aimen Zlitni
- , Gayatri Gowrishankar
- & Sanjiv Sam Gambhir
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Article
| Open AccessA comparative genomics study of 23 Aspergillus species from section Flavi
Aspergillus fungi classified within the section Flavi include harmful and beneficial species. Here, Kjærbølling et al. analyse the genomes of 23 Flavi species, showing high genetic diversity and potential for synthesis of over 13,700 CAZymes and 1600 secondary metabolites.
- Inge Kjærbølling
- , Tammi Vesth
- & Mikael R. Andersen
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Article
| Open AccessPlant metabolism of nematode pheromones mediates plant-nematode interactions
Small molecules in the rhizosphere regulate interactions between plants and other organisms. Here the authors show that an ascaroside pheromone secreted by plant-parasitic nematodes is converted by host plant peroxisomal β-oxidation into shorter side-chained ascarosides that repel nematodes.
- Murli Manohar
- , Francisco Tenjo-Castano
- & Frank C. Schroeder
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Article
| Open AccessROCK inhibitors upregulate the neuroprotective Parkin-mediated mitophagy pathway
Damaged mitochondria are known to cause neuronal death, suggesting clearance as a potential therapy. Here, Moskal et al. show that ROCK inhibitors promote Parkin recruitment and mitophagy and have neuroprotective effects in fruit flies challenged with a toxin that induces mitochondrial damage.
- Natalia Moskal
- , Victoria Riccio
- & G. Angus McQuibban
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Article
| Open AccessSmall molecule degraders of the hepatitis C virus protease reduce susceptibility to resistance mutations
Targeted protein degradation (TPD) is a promising strategy for drug development. In this proof-of-concept study, the authors use telaprevir, which binds hepatitis C virus (HCV) NS3/4A protease, to target the protease for protein degradation, and show inhibition of wildtype as well as drug resistant HCV.
- Mélissanne de Wispelaere
- , Guangyan Du
- & Priscilla L. Yang
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Article
| Open AccessGram-scale total synthesis of teixobactin promoting binding mode study and discovery of more potent antibiotics
The presence of the unnatural amino acid l-allo-enduracidine in the cyclic scaffold of teixobactin complicates its total synthesis. Here, the authors developed a convergent strategy for the scalable synthesis teixobactin and found two potent analogous.
- Yu Zong
- , Fang Fang
- & Yu Rao
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Article
| Open AccessSmall-molecule targeting of MUSASHI RNA-binding activity in acute myeloid leukemia
The RNA binding protein MUSASHI-2 (MSI2) is a potential therapeutic target for acute myeloid leukemia. Here the authors identify a small molecule inhibitor of MSI2 and characterize its effects in a murine leukemia model.
- Gerard Minuesa
- , Steven K. Albanese
- & Michael G. Kharas
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Article
| Open AccessDirected self-assembly of herbal small molecules into sustained release hydrogels for treating neural inflammation
There is interest in the development of drug-based hydrogels for responsive sustained drug release. Here, the authors report on the self-assembly of natural small molecule, rhein, into hydrogels and the application of the hydrogels as stable controlled release agents for neuro-inflammatory therapy
- Jun Zheng
- , Rong Fan
- & Yang Wang
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Article
| Open AccessSynthetic ligands for PreQ1 riboswitches provide structural and mechanistic insights into targeting RNA tertiary structure
RNA sensors—Riboswitches—respond to the binding of small molecules ligands through structure modification. Here the authors identify synthetic small molecules that bind and regulate the activity of PreQ1 Riboswitches despite having no obvious chemical similarity to the cognate ligand.
- Colleen M. Connelly
- , Tomoyuki Numata
- & John S. Schneekloth Jr.
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Article
| Open AccessNucleoside analogue activators of cyclic AMP-independent protein kinase A of Trypanosoma
Protein kinase A (PKA) is typically activated by cAMP. Here, Bachmaier et al. show that PKA of Trypanosoma is activated by nucleoside-related ligands, explain the ligand selectivity swap by a co-crystal structure of trypanosome PKAR, and identify potential downstream targets by phosphoproteomics.
- Sabine Bachmaier
- , Yuri Volpato Santos
- & Michael Boshart
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Article
| Open AccessImaging inflammation using an activated macrophage probe with Slc18b1 as the activation-selective gating target
Attempts to image activated macrophages in vivo have been hampered by selectivity and delivery problems. Here the authors develop a small molecule fluorescent probe specific to activated M1 and M2 macrophages, identify the orphan receptor Slc18b1/SLC18B1 as the mechanism of uptake, and use it to image atherosclerosis in mice.
- Sung-Jin Park
- , Beomsue Kim
- & Young-Tae Chang
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Article
| Open AccessDifferential PROTAC substrate specificity dictated by orientation of recruited E3 ligase
PROTACs enable targeted protein degradation by recruiting an E3 ligase to a specific substrate but the determinants of selectivity are not fully understood. Here, the authors show that varying the linker between warhead and E3 ligand and the orientation of the E3 ligase allow tuning PROTAC selectivity toward different p38 isoforms.
- Blake E. Smith
- , Stephen L. Wang
- & Craig M. Crews
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Article
| Open AccessHost-targeted niclosamide inhibits C. difficile virulence and prevents disease in mice without disrupting the gut microbiota
Clostridium difficile causes diarrhea and colitis by producing up to three different protein toxins. Here, Tam et al. show that an anthelmintic drug, niclosamide, inhibits the pathogenesis of all three toxins by targeting a host process required for toxin entry into host cells, without disrupting the gut microbiota.
- John Tam
- , Therwa Hamza
- & Roman A. Melnyk
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Article
| Open AccessDesign of Peptoid-peptide Macrocycles to Inhibit the β-catenin TCF Interaction in Prostate Cancer
Small molecules and peptide inhibitors have their benefits and faults when it comes to inhibiting protein-protein interactions. Here, the authors designed a peptoid-peptide hybrid that inhibited β-catenin/TCF interactions, leading to inhibition of Wnt signalling in models of prostate cancer.
- Jeffrey A. Schneider
- , Timothy W. Craven
- & Susan K. Logan
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Article
| Open AccessStructure-based redesign of docking domain interactions modulates the product spectrum of a rhabdopeptide-synthesizing NRPS
Rhabdopeptides are synthesized by non-ribosomal peptide synthetases (NRPSs) and the multiple NRPS subunits interact through docking domains (DD). Here the authors provide insights into DD interaction patterns and present the structures of three N-terminal docking domains (NDD) and a NDD-CDD complex and derive a set of recognition rules for DD interactions.
- Carolin Hacker
- , Xiaofeng Cai
- & Jens Wöhnert
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Article
| Open AccessChemical and structural studies provide a mechanistic basis for recognition of the MYC G-quadruplex
Targeting noncoding nucleic acids with small molecules represents an important and significant challenge in chemical biology and drug discovery. Here the authors characterize DC-34, a small molecule that exhibits selective binding to specific G4 structures, and provide a structural basis for its selectivity
- David R. Calabrese
- , Xiang Chen
- & John S. Schneekloth Jr.
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Article
| Open AccessClopidogrel as a donor probe and thioenol derivatives as flexible promoieties for enabling H2S biomedicine
Hydrogen sulphide (H2S) is a gaseous signalling molecule, which has shown therapeutic value. Here, the authors show that a thioenol metabolite of the antithrombotic drug clopidogrel is an efficient H2S donor and masked thioenols can be linked to existing compounds to develop H2S-releasing agents.
- Yaoqiu Zhu
- , Elkin L. Romero
- & Bin Geng
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Article
| Open AccessPeptide-guided functionalization and macrocyclization of bioactive peptidosulfonamides by Pd(II)-catalyzed late-stage C–H activation
Aryl sulfonamides and sultams are important pharmacophores in medicinal chemistry. Here, the authors report a practical palladium-catalyzed C–H activation assisted by amino-acid residues in the substrate leading to arylsulfonamides and bioactive peptidosulfonamide macrocycles.
- Jian Tang
- , Hongfei Chen
- & Huan Wang
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Article
| Open AccessTargeting repair pathways with small molecules increases precise genome editing in pluripotent stem cells
Small molecule inhibitors can influence the choice of repair pathways, enhancing nucleotide substitution and gene integration in CRISPR-mediated genome editing. Here the authors introduce CRISPY, a mix of small molecules that can enhance precise editing with Cpf1 and Cas9D10A in hiPSCs.
- Stephan Riesenberg
- & Tomislav Maricic
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Article
| Open AccessA fluorescence anisotropy assay to discover and characterize ligands targeting the maytansine site of tubulin
Microtubule-targeting agents are used successfully as anticancer therapeutics. Here authors develop a fluorescence-anisotropy-based assay to identify and characterize ligands for the maytansine site of tubulin and provide crystal structures of identified ligands in complex with tubulin.
- Grégory Menchon
- , Andrea E. Prota
- & Michel O. Steinmetz
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Article
| Open AccessModulation of Hoogsteen dynamics on DNA recognition
DNA is found in a dynamic equilibrium between standard Watson-Crick (WC) base pairs and non-standard Hoogsteen (HG) base pairs. Here the authors describe the influence of echinomycin and actinomycin D ligands binding on the HG-WC base pair dynamics in DNA.
- Yu Xu
- , James McSally
- & Hashim M. Al-Hashimi
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Article
| Open AccessSmall molecules promote CRISPR-Cpf1-mediated genome editing in human pluripotent stem cells
Precise genome editing in human pluripotent stem cells requires the development of methods for rapid and efficient genetic manipulation. Here, the authors screen for small molecules that enhance CRISPR-Cpf1-mediated genome engineering.
- Xiaojie Ma
- , Xi Chen
- & Saiyong Zhu
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Article
| Open AccessUSP15-dependent lysosomal pathway controls p53-R175H turnover in ovarian cancer cells
Gain-of-function mutants of p53 are important for cancer development and strategies to target specifically these isoforms are being investigated. Here the authors report that USP15 is a deubiquitinase specifically regulating p53-R175H levels that can be targeted by a small molecule.
- Achuth Padmanabhan
- , Nicholes Candelaria
- & JoAnne S. Richards
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Article
| Open AccessA DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage
Activation of the tumor suppressor p53 is a promising approach in cancer therapy. Here, the authors discover a series of small molecule dihydroorotate dehydrogenase (DHODH) inhibitors that increase p53 synthesis and reduce tumor growth in synergy with the common mdm2 inhibitor nutlin3.
- Marcus J. G. W. Ladds
- , Ingeborg M. M. van Leeuwen
- & Sonia Laín
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Article
| Open AccessRapid measurement of inhibitor binding kinetics by isothermal titration calorimetry
There is growing evidence that the kinetics of interactions between inhibitors and their targets can strongly impact therapeutic efficacy. Here the authors describe an isothermal titration calorimetry-based method that can rapidly quantify inhibition kinetics and measure sub-nM binding affinities.
- Justin M. Di Trani
- , Stephane De Cesco
- & Anthony K. Mittermaier
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Correspondence
| Open AccessCorrespondence: Compound 17b and formyl peptide receptor biased agonism in relation to cardioprotective effects in ischaemia-reperfusion injury
- Agostino Cilibrizzi
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Article
| Open AccessA 1-phytase type III effector interferes with plant hormone signaling
Plant pathogens translocate type III effector (T3E) proteins that may be recognized by plants to trigger immunity. Here, the authors show that the Xanthomonas T3E XopH possesses a novel 1-phytase activity that is required for XopH-mediated immunity of plants carrying the Bs7 resistance gene.
- Doreen Blüher
- , Debabrata Laha
- & Ulla Bonas
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Article
| Open AccessMolecular basis of differential 3′ splice site sensitivity to anti-tumor drugs targeting U2 snRNP
Several families of natural compounds target core components of the pre-mRNA splicing machinery and display anti-tumor activity. Here the authors show that particular sequence features can be linked to drug response, and that drugs with very similar chemical structures display substantially different effects on splicing regulation.
- Luisa Vigevani
- , André Gohr
- & Juan Valcárcel
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Article
| Open AccessMulticomponent mapping of boron chemotypes furnishes selective enzyme inhibitors
Heteroatom-rich organoboron compounds are promising modulators of enzyme activity. Here, the authors report a library of aminocyanoboronates as serine hydrolases inhibitors with the most potent compound showing in vivo and in vitro nanomolar activity and high selectivity towards human ABHD3 hydrolase.
- Joanne Tan
- , Armand B. Cognetta III
- & Andrei K. Yudin
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Article
| Open AccessDual protein kinase and nucleoside kinase modulators for rationally designed polypharmacology
Masitinib is a protein kinase inhibitor that sensitises refractory pancreatic adenocarcinoma cells to treatment with the nucleoside analog gemcitabine. Here the authors show that Masitinib activates deoxycytidine kinase to enhance phosphorylation of nucleoside analogue pro-drugs, increasing their potency.
- Kahina Hammam
- , Magali Saez-Ayala
- & Patrice Dubreuil
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Article
| Open AccessA potent small-molecule inhibitor of the DCN1-UBC12 interaction that selectively blocks cullin 3 neddylation
Cullins are central components of the ubiquitin-proteosome system and are activated via a neddylation process mediated by the DCN1–UBC12 complex. Here, the authors develop a small molecule inhibitor of the DCN1–UBC12 interaction that specifically blocks cullin 3 neddylation and can be used to probe the cellular function of cullin 3.
- Haibin Zhou
- , Jianfeng Lu
- & Shaomeng Wang
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Article
| Open AccessHomo-PROTACs: bivalent small-molecule dimerizers of the VHL E3 ubiquitin ligase to induce self-degradation
Targeting the ubiquitin proteasome system to modulate protein homeostasis using small molecules has promising therapeutic potential. Here the authors describe Homo-PROTACS: small molecules that can induce the homo-dimerization of E3 ubiquitin ligases and cause their proteasome-dependent degradation.
- Chiara Maniaci
- , Scott J. Hughes
- & Alessio Ciulli
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Article
| Open AccessControl of leucine-dependent mTORC1 pathway through chemical intervention of leucyl-tRNA synthetase and RagD interaction
Leucyl-tRNA synthetase (LRS) is a leucine sensor of the mTORC1 pathway. Here, the authors identify inhibitors of the GTPase activating function of LRS, not affecting its catalytic activity, and demonstrate that the leucine sensor function of LRS can be a new target for mTORC1 inhibition.
- Jong Hyun Kim
- , Chulho Lee
- & Sunghoon Kim
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Article
| Open AccessExploiting a novel conformational switch to control innate immunity mediated by complement protein C3a
Complement C3a is an important protein in innate and adaptive immunity, but its roles in vivo are unclear. Here the authors develop novel chemical agonists and antagonists for the C3a receptor, and show that they modulate mast cell degranulation and inflammation in a rat paw edema model
- Rink-Jan Lohman
- , Johan K. Hamidon
- & David P. Fairlie
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Article
| Open AccessCLK-dependent exon recognition and conjoined gene formation revealed with a novel small molecule inhibitor
The phosphorylation of serine/arginine-rich proteins by CDC-like kinase is a central regulatory mechanism for RNA splicing reactions. Here, the authors synthesize a novel small molecule CLK inhibitor and map CLK-responsive alternative splicing events and discover an effect on conjoined gene transcription.
- Tyler Funnell
- , Shinya Tasaki
- & Samuel Aparicio