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| Open AccessSubstrate promiscuity of inositol 1,4,5-trisphosphate kinase driven by structurally-modified ligands and active site plasticity
InsP3 3-kinase phosphorylates 1,4,5-trisphosphate (InsP3) specifically at its secondary 3-hydroxyl group to generate a tetrakisphosphate. Here, the authors used a combination of methods to survey InsP3 3-kinase ligand specificity and determined that IP3K specificity surpasses that of its natural substrate, allowing it to bind diverse ligands with a primary hydroxyl in the reactive position and based on a carbohydrate moiety.
- María Ángeles Márquez-Moñino
- , Raquel Ortega-García
- & Beatriz González
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Article
| Open AccessA conformation-locking inhibitor of SLC15A4 with TASL proteostatic anti-inflammatory activity
The authors identify feeblin, an inhibitory compound of the proinflammatory TLR7/8/9-IRF5 pathway with therapeutic potential, which acts by binding SLC15A4 via an allosteric mechanism mediating degradation of its signaling partner TASL.
- Andras Boeszoermenyi
- , Léa Bernaleau
- & Giulio Superti-Furga
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Article
| Open AccessGenetically encoded discovery of perfluoroaryl macrocycles that bind to albumin and exhibit extended circulation in vivo
Peptide-based therapeutics are promising therapeutic modalities, however, their prevalent drawback is poor circulation half-life in vivo. Here, the authors report the selection of albumin-binding macrocyclic peptides from genetically encoded libraries of peptides modified by perfluoroaryl-cysteine chemistry, with decafluoro-diphenylsulfone.
- Jeffrey Y. K. Wong
- , Arunika I. Ekanayake
- & Ratmir Derda
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Article
| Open AccessPharmacological perturbation of the phase-separating protein SMNDC1
SMNDC1 is a splicing factor that binds arginine methylation with its Tudor domain. Here, the authors study the protein’s phase-separating behavior and develop small-molecule Tudor domain inhibitors that perturb SMNDC1 function.
- Lennart Enders
- , Marton Siklos
- & Stefan Kubicek
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Article
| Open AccessRapid planning and analysis of high-throughput experiment arrays for reaction discovery
High-throughput experimentation is an increasingly important tool in reaction discovery, while there remains a need for software solutions to navigate data-rich experiments. Here the authors report phactor™, a software that facilitates the performance and analysis of high-throughput experimentation in a chemical laboratory.
- Babak Mahjour
- , Rui Zhang
- & Tim Cernak
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Article
| Open AccessReference compounds for characterizing cellular injury in high-content cellular morphology assays
Cellular nuisance compounds are a burden in chemical biology and drug screening. Here the authors profile prototypical cytotoxic and nuisance compounds using the cell painting assay to systematically characterise cellular morphologies associated with compound-dependent cellular injury and nuisance activity.
- Jayme L. Dahlin
- , Bruce K. Hua
- & Bridget K. Wagner
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Article
| Open AccessA covalent BTK ternary complex compatible with targeted protein degradation
Bridging covalent ligand discovery with chimeric degrader design has emerged as a mechanism to target proteins that lack enzymatic activity or are intractable. Here, the authors use biochemical and cellular tools to deconvolute the role of covalent modification in targeted protein degradation using Bruton’s tyrosine kinase.
- James Schiemer
- , Andrew Maxwell
- & Matthew F. Calabrese
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Article
| Open AccessAccelerating inhibitor discovery for deubiquitinating enzymes
Deubiquitinases (DUBs) are key signaling enzymes, many of which lack selective inhibitors. Chan et al. pair a DUB-focused covalent library to mass spectrometry activity-based protein profiling, leading to selective hits against 23 endogenous DUBs and a first-in-class VCPIP1 probe with nanomolar potency.
- Wai Cheung Chan
- , Xiaoxi Liu
- & Sara J. Buhrlage
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Article
| Open AccessA FRET-based respirasome assembly screen identifies spleen tyrosine kinase as a target to improve muscle mitochondrial respiration and exercise performance in mice
Mitochondrial supercomplex assembly may efficiently supply energy, yet its role remains controversial. Here, the authors show that SYK inhibitors increase supercomplex assembly and mitochondrial respiration in cells and can enhance exercise performance in mice.
- Ami Kobayashi
- , Kotaro Azuma
- & Satoshi Inoue
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Article
| Open AccessFilamin A organizes γ‑aminobutyric acid type B receptors at the plasma membrane
GABAB receptors mediate the effects of the main inhibitory neurotransmitter in the brain. Here, authors identify the cytoskeletal protein filamin A as a key player that controls the exact location and function of GABAB receptors at the cell surface.
- Marie-Lise Jobin
- , Sana Siddig
- & Davide Calebiro
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Article
| Open AccessConstruction of a synthetic methodology-based library and its application in identifying a GIT/PIX protein–protein interaction inhibitor
Chemical libraries with skeleton diversity are important for drug discovery. Here, the authors establish a synthetic methodology-based compound library (SMBL), and apply it to identify a small-molecule inhibitor to interrupt a challenging target: the protein–protein interaction (PPI) of GIT1/β-Pix.
- Jing Gu
- , Rui-Kun Peng
- & Qin Ouyang
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Article
| Open AccessIncreased slow dynamics defines ligandability of BTB domains
Here, the authors discover that ligandability of BTB domains correlates with the presence of μs-ms time scale dynamics. This finding suggests that protein dynamics may be a broadly applicable tool in drug discovery to assess the ligandability of novel and challenging targets.
- Vladlena Kharchenko
- , Brian M. Linhares
- & Łukasz Jaremko
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Article
| Open AccessGlycolytic flux control by drugging phosphoglycolate phosphatase
Targeting cellular glucose metabolism is a therapeutic strategy in human diseases such as autoimmunity or cancer. Here, the authors demonstrate the druggability of phosphoglycolate phosphatase, and validate an alternative approach to control glycolysis.
- Elisabeth Jeanclos
- , Jan Schlötzer
- & Antje Gohla
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Article
| Open AccessChemical space docking enables large-scale structure-based virtual screening to discover ROCK1 kinase inhibitors
Virtual screening of huge libraries is successful in identifying drug leads. Here, the authors describe a computational strategy, Chemical Space Docking, which combines docking with a reaction-based search of compounds, thereby enabling the exploration of billions of compounds and beyond.
- Paul Beroza
- , James J. Crawford
- & Christian Lemmen
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Article
| Open AccessSelective macrocyclic peptide modulators of Lys63-linked ubiquitin chains disrupt DNA damage repair
Finding a selective modulator of Lys63-linked ubiquitin chains has proven very challenging. Here, the authors develop potent macrocyclic peptide binders of Lys63-linked di-ubiquitin chains that interrupt DNA damage repair and lead to apoptotic cell death.
- Ganga B. Vamisetti
- , Abhishek Saha
- & Ashraf Brik
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Article
| Open AccessVisualizing inflammation with an M1 macrophage selective probe via GLUT1 as the gating target
Studying the specific roles of macrophage subsets has been hampered by a lack of subset-specific probes. Here the authors report an M1 selective fluorescent probe named CDr17, and demonstrate the suitability of this probe for tracking M1 macrophages in vivo.
- Heewon Cho
- , Haw-Young Kwon
- & Young-Tae Chang
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Article
| Open AccessSynthesis and direct assay of large macrocycle diversities by combinatorial late-stage modification at picomole scale
Macrocycles have potential as therapeutics, but their libraries are currently not large enough for high-throughput screening. Here, the authors show a combinatorial approach to generate a library of almost 20’000 macrocycles by conjugating carboxylic-acid fragments to macrocyclic scaffolds, identifying nanomolar inhibitors against thrombin and binders of MDM2.
- Sevan Habeshian
- , Manuel Leonardo Merz
- & Christian Heinis
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Article
| Open AccessIdentification of oleoylethanolamide as an endogenous ligand for HIF-3α
Whether hypoxia-inducible factors (HIFs) can be directly regulated by endogenous small molecules is a long-standing question. Here authors identified the metabolite oleoylethanolamide as a HIF-3α ligand and further revealed its mechanism of action.
- Xiaotong Diao
- , Fei Ye
- & Dalei Wu
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Article
| Open AccessDiscovery of a dual Ras and ARF6 inhibitor from a GPCR endocytosis screen
While Ras is a promising target for cancer therapy, development of inhibitors targeting Ras signaling has proven challenging. Here, the authors report the discovery of Rasarfin, a small molecule from a phenotypic screen on G protein-coupled receptor (GPCR) endocytosis that acts as a dual Ras and ARF6 inhibitor.
- Jenna Giubilaro
- , Doris A. Schuetz
- & Stéphane A. Laporte
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| Open AccessRapid discovery of self-assembling peptides with one-bead one-compound peptide library
Self-assembling peptides have a range of potential applications but developing self-assembling sequences can be challenging. Here, the authors report on a one-bead one-compound combinatorial library where fluorescence is used to detect the potential for self-assembly and identified candidates are evaluated.
- Pei-Pei Yang
- , Yi-Jing Li
- & Kit S. Lam
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Article
| Open AccessERRγ enhances cardiac maturation with T-tubule formation in human iPSC-derived cardiomyocytes
Cardiomyocytes (CMs) derived from human induced pluripotent stem cells (hiPSCs) suffer from limited maturation. Here the authors identify ERRγ agonist as a factor that enhances cardiac morphological, metabolic, contractile and electrical maturation of hiPSC-derived CMs with T-tubule formation.
- Kenji Miki
- , Kohei Deguchi
- & Yoshinori Yoshida
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| Open AccessAn all-to-all approach to the identification of sequence-specific readers for epigenetic DNA modifications on cytosine
Identifying readers of epigenetic marks is a critical step for understanding the role of epigenetic marks in biology. Here, the authors applied DAPPL, an all-to-all approach to profile the interactions between TFs and epigenetic modified DNA libraries.
- Guang Song
- , Guohua Wang
- & Heng Zhu
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| Open AccessDiscovery of gramicidin A analogues with altered activities by multidimensional screening of a one-bead-one-compound library
The strong hemolytic activity and mammalian cytotoxicity of gramicidin A, a peptide antibiotic, has hindered its non-topical clinical application. Here, the authors report a high-throughput strategy for the discovery of gramicidin A analogues with altered biological activity profiles.
- Yuri Takada
- , Hiroaki Itoh
- & Masayuki Inoue
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| Open AccessSplit Intein-Mediated Protein Ligation for detecting protein-protein interactions and their inhibition
Protein-protein interactions are fundamental to the regulation of protein activity and cellular phyisology. Here the authors present Split Intein-Mediated Protein Ligation, which uses bait and prey proteins fused to intein fragments to generate single intact proteins upon interaction.
- Zhong Yao
- , Farzaneh Aboualizadeh
- & Igor Stagljar
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Article
| Open AccessAn amber obligate active site-directed ligand evolution technique for phage display
Most epigenetic regulator inhibitors target tunnels of active sites, rather than the peptide binding groove, leading to concerns with low selectivity. Here the authors use an amber obligate phage library to rapidly identify isoform-selective inhibitors of SIRT2.
- Jeffery M. Tharp
- , J. Trae Hampton
- & Wenshe Ray Liu
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Article
| Open AccessSmall molecules that inhibit TNF signalling by stabilising an asymmetric form of the trimer
While biologics have been successfully applied in TNF antagonist treatments, there are no clinically approved small molecules that target TNF. Here, the authors discover potent small molecule inhibitors of TNF, elucidate their molecular mechanism, and demonstrate TNF inhibition in vitro and in vivo.
- James O’Connell
- , John Porter
- & Alastair Lawson
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Article
| Open AccessInsights into real-time chemical processes in a calcium sensor protein-directed dynamic library
Dynamic combinatorial chemistry (DCC) is instrumental in the discovery of ligands for pharmaceutical targets. Here, the authors adapted DCC to work at 4 degrees Celsius and used it to identify a ligand for Neuronal Calcium Sensor-1 that promotes NCS-1/Ric8a protein-protein interaction.
- Andrea Canal-Martín
- , Javier Sastre
- & Ruth Pérez-Fernández
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Article
| Open AccessBacterial glycosyltransferase-mediated cell-surface chemoenzymatic glycan modification
Glycan molecules can be modified directly on the cell surface via chemoenzymatic approaches. Here, the authors employ a set of four bacterial glycosyltransferases to develop a live cell-based killing assay to probe host cell glycan-mediated influenza A virus infection.
- Senlian Hong
- , Yujie Shi
- & Peng Wu
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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 AccessDesign strategy for serine hydroxymethyltransferase probes based on retro-aldol-type reaction
The enzyme serine hydroxymethyltransferase (SHMT) has been implicated in several diseases, however is hard to investigate. Here, the authors used a design strategy based on the retro-aldol-type reaction catalyzed by SHMT to develop SHMT-responsive fluorescence and 19F NMR molecular probes.
- Hiroshi Nonaka
- , Yuki Nakanishi
- & Shinsuke Sando
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| Open AccessMultidirectional desymmetrization of pluripotent building block en route to diastereoselective synthesis of complex nature-inspired scaffolds
Methods enabling the synthesis of diverse collections of nature-inspired compounds with potential medicinal use are sought after in drug design. Here, the authors report a build/couple/pair strategy to efficiently construct chiral polycyclic scaffolds and show their diversification for drug discovery screening.
- Vunnam Srinivasulu
- , Paul Schilf
- & Taleb H. Al-Tel
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Article
| Open AccessA hPSC-based platform to discover gene-environment interactions that impact human β-cell and dopamine neuron survival
Diseases such as diabetes and Parkinson's manifest based on interactions between genes and environment. Here, the authors find among a panel of cell types that propargite, a common pesticide, induces pancreatic β-cell and dopamine neuron death and that loss of the gene GSTT1 confers hypersensitivity.
- Ting Zhou
- , Tae Wan Kim
- & Shuibing Chen
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Article
| Open AccessDRUG-seq for miniaturized high-throughput transcriptome profiling in drug discovery
RNA-seq is a powerful tool to investigate how drugs affect the transcriptome but library construction can be costly. Here the authors introduce DRUG-seq, an automated platform for high-throughput transcriptome profiling.
- Chaoyang Ye
- , Daniel J. Ho
- & Ajamete Kaykas
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| Open AccessSmall molecule inhibitors of RAS-effector protein interactions derived using an intracellular antibody fragment
Intracellular antibodies can inhibit disease-relevant protein interactions, but inefficient cellular uptake limits their utility. Using a RAS-targeting intracellular antibody as a screening tool, the authors here identify small molecules that inhibit RAS-effector interactions and readily penetrate cells.
- Camilo E. Quevedo
- , Abimael Cruz-Migoni
- & Terence H. Rabbitts
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| 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 AccessCell-based glycan arrays for probing glycan–glycan binding protein interactions
Glycans, interaction platforms protruding from the surface of cells, are hard to study due to their diverse architecture. Here, the authors present a method to obtain cells carrying defined glycans, which can then be used to find proteins specifically recognizing these tags.
- Jennie Grace Briard
- , Hao Jiang
- & Peng Wu
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Article
| Open AccessTargeted NUDT5 inhibitors block hormone signaling in breast cancer cells
NUDIX hydrolases are an important family of nucleotide-metabolizing enzymes. Here, the authors identify potent, small molecule inhibitors of NUDT5, which is implicated in ADP-ribose and 8-oxo-guanine metabolism, and confirm its role in gene regulation and proliferation in breast cancer cells.
- Brent D. G. Page
- , Nicholas C. K. Valerie
- & Thomas Helleday
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Article
| Open AccessAssay interference and off-target liabilities of reported histone acetyltransferase inhibitors
A substantial obstacle in basic research is the use of poorly validated tool compounds with purported useful biological functions. Here, the authors systematically profile widely used histone acetyltransferase inhibitors and find that the majority are nonselective interference compounds.
- Jayme L. Dahlin
- , Kathryn M. Nelson
- & Michael A. Walters
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Article
| Open AccessROCKII inhibition promotes the maturation of human pancreatic beta-like cells
Our incomplete understanding of how pancreatic beta cells form limits the generation of beta-like cells from human pluripotent stem cells (hPSC). Here, the authors identify a ROCKII inhibitor H1152 as increasing insulin secreting cells from hPSCs and improving beta-cell maturation on transplantation in vivo.
- Zaniar Ghazizadeh
- , Der-I Kao
- & Shuibing Chen
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Article
| Open AccessUncoupling conformational states from activity in an allosteric enzyme
Active and inactive state ATP-phosphoribosyltransferases (ATP-PRTs) are believed to have different conformations. Here the authors show that in both states, ATP-PRT has a similar structural arrangement, suggesting that dynamic alterations are involved in ATP-PRT regulation by allosteric modulators.
- João P. Pisco
- , Cesira de Chiara
- & Luiz Pedro S. de Carvalho
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Article
| Open AccessA multi-crystal method for extracting obscured crystallographic states from conventionally uninterpretable electron density
Building a ligand into a weak region of an electron density map of a protein is a subjective process. Here, the authors present a new method to obtain a clear electron density for a bound ligand based on multi-crystal experiments and 3D background correction.
- Nicholas M. Pearce
- , Tobias Krojer
- & Frank von Delft
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Article
| Open AccessImpact of genetic background and experimental reproducibility on identifying chemical compounds with robust longevity effects
Irreproducibility of biological findings is a major challenge for drug development. Here the authors examine the lifespans of 22 worm strains in three different laboratories and the effects of ten known chemicals to assess reproducibility in the face of variations in genetic background, chemical treatment and lab environment.
- Mark Lucanic
- , W. Todd Plummer
- & Patrick C. Phillips
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Article
| Open AccessA human genome-wide loss-of-function screen identifies effective chikungunya antiviral drugs
Chikungunya virus is a mosquito transmitted untreatable emergent pathogen that causes joint pain and fever. Here the authors perform a host genome-wide loss-of-function screen to identify targets for chikungunya antiviral drugs and validate hits using a mouse model of chikungunya infection.
- Alexander Karlas
- , Stefano Berre
- & Marc Lecuit
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Article
| Open AccessCETSA screening identifies known and novel thymidylate synthase inhibitors and slow intracellular activation of 5-fluorouracil
Drugs therapeutic efficacy relies on their capability of binding the relevant targets in a physiological environment, which has so far been hard to measure. Here, the authors present a compound library screen based on a target engagement assay that reports on protein stability upon ligands binding in cell.
- Helena Almqvist
- , Hanna Axelsson
- & Pär Nordlund
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Article
| Open AccessPharmaceutical screen identifies novel target processes for activation of autophagy with a broad translational potential
Autophagy is a homeostatic process that could be a potential drug target in the treatment of disease. Here the authors identify in a pharmaceutical screen flubendazole as an inducer of autophagy initiation and flux by affecting microtubules, mTOR, TFEB and Beclin 1 activity.
- Santosh Chauhan
- , Zahra Ahmed
- & Vojo Deretic