810 results match your criteria Cell chemical biology[Journal]


A Systematic Analysis of Mosquito-Microbiome Biosynthetic Gene Clusters Reveals Antimalarial Siderophores that Reduce Mosquito Reproduction Capacity.

Cell Chem Biol 2020 Jun 29. Epub 2020 Jun 29.

Department of Chemistry, Duke University, Durham, NC, USA; Department of Molecular Genetics and Microbiology, Duke University, Durham, NC, USA. Electronic address:

Advances in infectious disease control strategies through genetic manipulation of insect microbiomes have heightened interest in microbially produced small molecules within mosquitoes. Herein, 33 mosquito-associated bacterial genomes were mined and over 700 putative biosynthetic gene clusters (BGCs) were identified, 135 of which belong to known classes of BGCs. After an in-depth analysis of the 135 BGCs, iron-binding siderophores were chosen for further investigation due to their high abundance and well-characterized bioactivities. Read More

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http://dx.doi.org/10.1016/j.chembiol.2020.06.004DOI Listing

Profiling Substrate Promiscuity of Wild-Type Sugar Kinases for Multi-fluorinated Monosaccharides.

Cell Chem Biol 2020 Jun 30. Epub 2020 Jun 30.

Department of Chemistry, University of York, Heslington, York YO10 5DD, UK. Electronic address:

Fluorinated sugar-1-phosphates are of emerging importance as intermediates in the chemical and biocatalytic synthesis of modified oligosaccharides, as well as probes for chemical biology. Here we present a systematic study of the activity of a wide range of anomeric sugar kinases (galacto- and N-acetylhexosamine kinases) against a panel of fluorinated monosaccharides, leading to the first examples of polyfluorinated substrates accepted by this class of enzymes. We have discovered four new N-acetylhexosamine kinases with a different substrate scope, thus expanding the number of homologs available in this subclass of kinases. Read More

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http://dx.doi.org/10.1016/j.chembiol.2020.06.005DOI Listing

Monitoring Allosteric Interactions with CXCR4 Using NanoBiT Conjugated Nanobodies.

Cell Chem Biol 2020 Jun 29. Epub 2020 Jun 29.

Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, University of Nottingham, Nottingham NG7 2UH, UK; Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham and University of Nottingham, The Midlands, UK. Electronic address:

Camelid single-domain antibody fragments (nanobodies) offer the specificity of an antibody in a single 15-kDa immunoglobulin domain. Their small size allows for easy genetic manipulation of the nanobody sequence to incorporate protein tags, facilitating their use as biochemical probes. The nanobody VUN400, which recognizes the second extracellular loop of the human CXCR4 chemokine receptor, was used as a probe to monitor specific CXCR4 conformations. Read More

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http://dx.doi.org/10.1016/j.chembiol.2020.06.006DOI Listing

Parallel Glyco-SPOT Synthesis of Glycopeptide Libraries.

Cell Chem Biol 2020 Jun 29. Epub 2020 Jun 29.

Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, National Center for Functional Glycomics, CLS 11087 - 3 Blackfan Circle, Boston, MA 02115, USA. Electronic address:

Glycan recognition is typically studied using free glycans, but glycopeptide presentations represent more physiological conditions for glycoproteins. To facilitate studies of glycopeptide recognition, we developed Glyco-SPOT synthesis, which enables the parallel production of diverse glycopeptide libraries at microgram scales. The method uses a closed system for prolonged reactions required for coupling Fmoc-protected glycoamino acids, including O-, N-, and S-linked glycosides, and release conditions to prevent side reactions. Read More

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http://dx.doi.org/10.1016/j.chembiol.2020.06.007DOI Listing

Playing Tag with Your Favorite GPCR Using CRISPR.

Cell Chem Biol 2020 Jun;27(6):642-644

Laboratory of Chemical Biology and Signal Transduction, The Rockefeller University, 1230 York Ave., New York, NY, USA. Electronic address:

In this issue of Cell Chemical Biology, White et al. (2020) describe CRISPR/Cas9-mediated tagging of GPCRs and β-arrestin to provide a method to study receptor signaling in cells under conditions of endogenous genetic control. The strategy, when coupled with luminescence reporter and complementation technologies, provides new avenues to study GPCRs. Read More

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http://dx.doi.org/10.1016/j.chembiol.2020.06.001DOI Listing

Selective Inhibition of BFL1: It's All about Finding the Right Partner.

Cell Chem Biol 2020 Jun;27(6):639-642

Division of Oncology Research, Mayo Clinic, Rochester, MN 55905, USA; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA. Electronic address:

In this issue of Cell Chemical Biology, Harvey et al. (2020) identify 4E14, a sulfhydryl-containing N-acetyltryptophan analog that selectively disrupts binding to the previously undruggable anti-apoptotic BCL2 paralog BFL1, and elucidate a BFL1 conformational change that facilitates 4E14 interaction. These results provide insight that will accelerate development of BFL1 inhibitors. Read More

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http://dx.doi.org/10.1016/j.chembiol.2020.05.014DOI Listing

Peptide-Based PROTAC: The Predator of Pathological Proteins.

Cell Chem Biol 2020 Jun;27(6):637-639

Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA. Electronic address:

Qu et al. (2020) demonstrate a peptide-induced targeted degradation of the alpha-synuclein protein, a hallmark of Parkinson's disease. Using a modular three-component design, the target-protein-specific, cell-permeable peptide disposed of alpha-synuclein via the ubiquitin-proteasome pathway rather than the standard autophagy-lysosome pathway. Read More

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http://dx.doi.org/10.1016/j.chembiol.2020.06.002DOI Listing

Fusicoccin Keeps Getting Stickier: Modulation of an Adaptor Protein Interactome with a Molecular Glue Leads to Neurite Outgrowth.

Cell Chem Biol 2020 Jun;27(6):635-637

Department of Chemistry, University of California-Berkeley, Berkeley, CA 94720, USA. Electronic address:

Many traditional drugs inhibit enzyme function; in contrast, some naturally "sticky" small molecules can stabilize protein-protein interactions. In this issue of Cell Chemical Biology, Kaplan et al. (2020) explore regulation of the 14-3-3 interactome by a small-molecule molecular glue leading to neurite outgrowth through a polypharmacological mechanism. Read More

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http://dx.doi.org/10.1016/j.chembiol.2020.05.011DOI Listing

tRNA-Derived Fragments Can Serve as Arginine Donors for Protein Arginylation.

Cell Chem Biol 2020 Jun 11. Epub 2020 Jun 11.

Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address:

Arginyltransferase ATE1 mediates posttranslational arginylation and plays key roles in multiple physiological processes. ATE1 utilizes arginyl (Arg)-tRNA as the donor of Arg, putting this reaction into a direct competition with the protein synthesis machinery. Here, we address the question of ATE1- Arg-tRNA specificity as a potential mechanism enabling this competition in vivo. Read More

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http://dx.doi.org/10.1016/j.chembiol.2020.05.013DOI Listing

A Photo-clickable ATP-Mimetic Reveals Nucleotide Interactors in the Membrane Proteome.

Cell Chem Biol 2020 Jun 5. Epub 2020 Jun 5.

Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address:

ATP is an important energy metabolite and allosteric signal in health and disease. ATP-interacting proteins, such as P2 receptors, control inflammation, cell death, migration, and wound healing. However, identification of allosteric ATP sites remains challenging, and our current inventory of ATP-controlled pathways is likely incomplete. Read More

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http://dx.doi.org/10.1016/j.chembiol.2020.05.010DOI Listing

From Young to Old: AMPylation Hits the Brain.

Cell Chem Biol 2020 Jun 5. Epub 2020 Jun 5.

Department of Chemistry, Ludwig-Maximilians-Universität München, Butenandtstraße 5-13, 81377 München, Germany. Electronic address:

Protein post-translational modifications (PTMs) are implicated in numerous physiological processes and significantly contribute to complex regulatory networks of protein functions. Recently, a protein PTM called AMPylation was found to play a role in modulation of neurodevelopment and neurodegeneration. Combination of biochemical and chemical proteomic studies has uncovered the prevalence of this PTM in regulation of diverse metabolic pathways. Read More

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http://dx.doi.org/10.1016/j.chembiol.2020.05.009DOI Listing

An Isoform-Selective Modulator of Cryptochrome 1 Regulates Circadian Rhythms in Mammals.

Cell Chem Biol 2020 Jun 1. Epub 2020 Jun 1.

Institute of Transformative Bio-Molecules, Nagoya University, Nagoya 464-8601, Japan. Electronic address:

Cryptochrome 1 (CRY1) and CRY2 are core regulators of the circadian clock, and the development of isoform-selective modulators is important for the elucidation of their redundant and distinct functions. Here, we report the identification and functional characterization of a small-molecule modulator of the mammalian circadian clock that selectively controls CRY1. Cell-based circadian chemical screening identified a thienopyrimidine derivative KL201 that lengthened the period of circadian rhythms in cells and tissues. Read More

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http://dx.doi.org/10.1016/j.chembiol.2020.05.008DOI Listing

A Clickable APEX Probe for Proximity-Dependent Proteomic Profiling in Yeast.

Cell Chem Biol 2020 May 22. Epub 2020 May 22.

College of Chemistry and Molecular Engineering, Synthetic and Functional Biomolecules Center, Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Peking University, Beijing 100871, China; Peking-Tsinghua Center for Life Sciences, PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China. Electronic address:

The engineered ascorbate peroxidase (APEX) is a powerful tool for the proximity-dependent labeling of proteins and RNAs in live cells. Although widely use in mammalian cells, APEX applications in microorganisms have been hampered by the poor labeling efficiency of its biotin-phenol (BP) substrate. In this study, we sought to address this challenge by designing and screening a panel of alkyne-functionalized substrates. Read More

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http://dx.doi.org/10.1016/j.chembiol.2020.05.006DOI Listing

Structural Basis for the Binding Selectivity of Human CDY Chromodomains.

Cell Chem Biol 2020 May 26. Epub 2020 May 26.

Hubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, Wuhan, Hubei 430079, China; Structural Genomics Consortium, University of Toronto, 101 College Street, Toronto, ON M5G 1L7, Canada; Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address:

The CDY (chromodomain on the Y) proteins play an essential role in normal spermatogenesis and brain development. Dysregulation of their expression has been linked to male infertility and various neurological diseases. Like the chromodomains of HP1 and Polycomb, the CDY chromodomains also recognize the lysine-methylated ARKS motif embedded in histone and non-histone proteins. Read More

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http://dx.doi.org/10.1016/j.chembiol.2020.05.007DOI Listing

Enhancing the Antiviral Efficacy of RNA-Dependent RNA Polymerase Inhibition by Combination with Modulators of Pyrimidine Metabolism.

Cell Chem Biol 2020 Jun 21;27(6):668-677.e9. Epub 2020 May 21.

Department of Chemistry, Stanford University, Stanford, CA 94305, USA; Stanford Chemistry, Engineering and Medicine for Human Health (ChEM-H), Stanford University, Stanford, CA 94305, USA; Department of Chemical Engineering, Stanford University, Stanford, CA 94305, USA. Electronic address:

Genome-wide analysis of the mode of action of GSK983, a potent antiviral agent, led to the identification of dihydroorotate dehydrogenase as its target along with the discovery that genetic knockdown of pyrimidine salvage sensitized cells to GSK983. Because GSK983 is an ineffective antiviral in the presence of physiological uridine concentrations, we explored combining GSK983 with pyrimidine salvage inhibitors. We synthesized and evaluated analogs of cyclopentenyl uracil (CPU), an inhibitor of uridine salvage. Read More

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http://dx.doi.org/10.1016/j.chembiol.2020.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7241336PMC

Distinct Mechanisms of Resistance to a CENP-E Inhibitor Emerge in Near-Haploid and Diploid Cancer Cells.

Cell Chem Biol 2020 May 19. Epub 2020 May 19.

Laboratory of Chemistry and Cell Biology, The Rockefeller University, New York, NY 10065, USA. Electronic address:

Aberrant chromosome numbers in cancer cells may impose distinct constraints on the emergence of drug resistance-a major factor limiting the long-term efficacy of molecularly targeted therapeutics. However, for most anticancer drugs we lack analyses of drug-resistance mechanisms in cells with different karyotypes. Here, we focus on GSK923295, a mitotic kinesin CENP-E inhibitor that was evaluated in clinical trials as a cancer therapeutic. Read More

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http://dx.doi.org/10.1016/j.chembiol.2020.05.003DOI Listing

CRISPR Lights up In Situ Protein Evolution.

Cell Chem Biol 2020 May;27(5):475-478

Department of Pharmacology, University of Alberta, Edmonton, AB T6G 2R7, Canada. Electronic address:

In this issue of Cell Chemical Biology, Erdogan et al. (2020) describe a new CRISPR/Cas9-based strategy for performing directed evolution of mammalian proteins in situ. Using this technique to select functional mRuby3 variants within lysosomes, they identify mCRISPRed, a fluorescent protein that displays robust stability and activity at low pH. Read More

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http://dx.doi.org/10.1016/j.chembiol.2020.05.005DOI Listing

It Takes Two to Regenerate: Optimizing Custom Wnt Surrogates.

Cell Chem Biol 2020 May;27(5):473-475

Department of Early Discovery Biochemistry, Genentech, 1 DNA Way, South San Francisco, CA, USA. Electronic address:

In this issue of Cell Chemical Biology, Chen et al. (2020) present an antibody-based platform to generate Wnt agonists, offering multiple design principles for systematic investigation of Wnt activation. This study lays the groundwork to develop potent Wnt agonists for applications in regenerative medicine. Read More

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http://dx.doi.org/10.1016/j.chembiol.2020.05.004DOI Listing

Regulation of MIF Enzymatic Activity by an Allosteric Site at the Central Solvent Channel.

Cell Chem Biol 2020 Jun 19;27(6):740-750.e5. Epub 2020 May 19.

Department of Pharmacology, School of Medicine, Yale University, New Haven, CT 06510, USA; Yale Cancer Center, Yale School of Medicine, New Haven, CT 06510, USA. Electronic address:

In proteins with multiple functions, such as macrophage migration inhibitory factor (MIF), the study of its intramolecular dynamic network can offer a unique opportunity to understand how a single protein is able to carry out several nonoverlapping functions. A dynamic mechanism that controls the MIF-induced activation of CD74 was recently discovered. In this study, the regulation of tautomerase activity was explored. Read More

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http://dx.doi.org/10.1016/j.chembiol.2020.05.001DOI Listing

Targeting Two-Component Systems Uncovers a Small-Molecule Inhibitor of Salmonella Virulence.

Cell Chem Biol 2020 Apr 21. Epub 2020 Apr 21.

Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4L8, Canada; Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, ON L8S 4L8, Canada. Electronic address:

Salmonella serovars are leading causes of gastrointestinal disease and have become increasingly resistant to fluoroquinolone and cephalosporin antibiotics. Overcoming this healthcare crisis requires new approaches in antibiotic discovery and the identification of unique bacterial targets. In this work, we describe a chemical genomics approach to identify inhibitors of Salmonella virulence. Read More

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http://dx.doi.org/10.1016/j.chembiol.2020.04.005DOI Listing

A Cell-Based Target Engagement Assay for the Identification of Cereblon E3 Ubiquitin Ligase Ligands and Their Application in HDAC6 Degraders.

Cell Chem Biol 2020 May 14. Epub 2020 May 14.

School of Pharmacy, University of Wisconsin-Madison, Madison, WI 53705, USA; Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53705, USA. Electronic address:

Proteolysis-targeting chimeras (PROTACs) is a paradigm shift for small-molecule drug discovery. However, limited E3 ubiquitin ligase ligands with cellular activity are available. In vitro binding assays involve the expression and purification of a large amount of proteins and they often yield ligands that are inactive in cell-based assays due to poor cell permeability, stability, and other reasons. Read More

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http://dx.doi.org/10.1016/j.chembiol.2020.04.008DOI Listing

Identification of a Covalent Molecular Inhibitor of Anti-apoptotic BFL-1 by Disulfide Tethering.

Cell Chem Biol 2020 Jun 14;27(6):647-656.e6. Epub 2020 May 14.

Department of Pediatric Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA; Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA. Electronic address:

The BCL-2 family is composed of anti- and pro-apoptotic members that respectively protect or disrupt mitochondrial integrity. Anti-apoptotic overexpression can promote oncogenesis by trapping the BCL-2 homology 3 (BH3) "killer domains" of pro-apoptotic proteins in a surface groove, blocking apoptosis. Groove inhibitors, such as the relatively large BCL-2 drug venetoclax (868 Da), have emerged as cancer therapies. Read More

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http://dx.doi.org/10.1016/j.chembiol.2020.04.004DOI Listing

Chemoproteomic Profiling of a Pharmacophore-Focused Chemical Library.

Cell Chem Biol 2020 Jun 12;27(6):708-718.e10. Epub 2020 May 12.

Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan; School of Pharmacy, Fudan University, Shanghai 201203, China; Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Uji, Kyoto 611-0011, Japan. Electronic address:

Pharmacophore-focused chemical libraries are continuously being created in drug discovery programs, yet screening assays to maximize the usage of such libraries are not fully explored. Here, we report a chemical proteomics approach to reutilizing a focused chemical library of 1,800 indole-containing molecules for discovering uncharacterized ligand-protein pairs. Gel-based protein profiling of the library using a photo-affinity indole probe 1 enabled us to find new ligands for glyoxalase 1 (Glo1), an enzyme involved in the detoxification of methylglyoxal. Read More

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http://dx.doi.org/10.1016/j.chembiol.2020.04.007DOI Listing

A Plasma Protein Network Regulates PM20D1 and N-Acyl Amino Acid Bioactivity.

Cell Chem Biol 2020 May 11. Epub 2020 May 11.

Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford ChEM-H, Stanford University, Stanford, CA 94305, USA. Electronic address:

N-acyl amino acids are a family of cold-inducible circulating lipids that stimulate thermogenesis. Their biosynthesis is mediated by a secreted enzyme called PM20D1. The extracellular mechanisms that regulate PM20D1 or N-acyl amino acid activity in the complex environment of blood plasma remains unknown. Read More

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http://dx.doi.org/10.1016/j.chembiol.2020.04.009DOI Listing

Targeted Degradation of SLC Transporters Reveals Amenability of Multi-Pass Transmembrane Proteins to Ligand-Induced Proteolysis.

Cell Chem Biol 2020 Jun 7;27(6):728-739.e9. Epub 2020 May 7.

CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria; Center for Physiology and Pharmacology, Medical University of Vienna, 1090 Vienna, Austria. Electronic address:

With more than 450 members, the solute carrier (SLC) group of proteins represents the largest class of transporters encoded in the human genome. Their several-pass transmembrane domain structure and hydrophobicity contribute to the orphan status of many SLCs, devoid of known cargos or chemical inhibitors. We report that SLC proteins belonging to different families and subcellular compartments are amenable to induced degradation by heterobifunctional ligands. Read More

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http://dx.doi.org/10.1016/j.chembiol.2020.04.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303955PMC

Chlorcyclizine Inhibits Viral Fusion of Hepatitis C Virus Entry by Directly Targeting HCV Envelope Glycoprotein 1.

Cell Chem Biol 2020 Apr 30. Epub 2020 Apr 30.

Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892, USA. Electronic address:

Chlorcyclizine (CCZ) is a potent hepatitis C virus (HCV) entry inhibitor, but its molecular mechanism is unknown. Here, we show that CCZ directly targets the fusion peptide of HCV E1 and interferes with the fusion process. Generation of CCZ resistance-associated substitutions of HCV in vitro revealed six missense mutations in the HCV E1 protein, five being in the putative fusion peptide. Read More

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http://dx.doi.org/10.1016/j.chembiol.2020.04.006DOI Listing

Blockade of Oncogenic NOTCH1 with the SERCA Inhibitor CAD204520 in T Cell Acute Lymphoblastic Leukemia.

Cell Chem Biol 2020 Jun 7;27(6):678-697.e13. Epub 2020 May 7.

University of Parma, Department of Medicine and Surgery, Parma 43126, Italy. Electronic address:

The identification of SERCA (sarco/endoplasmic reticulum calcium ATPase) as a target for modulating gain-of-function NOTCH1 mutations in Notch-dependent cancers has spurred the development of this compound class for cancer therapeutics. Despite the innate toxicity challenge associated with SERCA inhibition, we identified CAD204520, a small molecule with better drug-like properties and reduced off-target Ca toxicity compared with the SERCA inhibitor thapsigargin. In this work, we describe the properties and complex structure of CAD204520 and show that CAD204520 preferentially targets mutated over wild-type NOTCH1 proteins in T cell acute lymphoblastic leukemia (T-ALL) and mantle cell lymphoma (MCL). Read More

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http://dx.doi.org/10.1016/j.chembiol.2020.04.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305996PMC

Specific Knockdown of α-Synuclein by Peptide-Directed Proteasome Degradation Rescued Its Associated Neurotoxicity.

Cell Chem Biol 2020 Jun 30;27(6):751-762.e4. Epub 2020 Apr 30.

Department of Neurobiology, Beijing Key Laboratory of Neural Regeneration and Repair, Beijing Institute of Brain Disorders, Key Laboratory for Neurodegenerative Disease of the Ministry of Education, Capital Medical University, #10 Xitoutiao, Youanmenwai, Beijing 100069, China. Electronic address:

α-Synuclein (α-syn) overload is strongly associated with Parkinson disease (PD), and reduction of the α-syn level by targeting the peptide-based system through the autophagy-lysosomal pathway (ALP) is a promising strategy to delay PD progression. However, if the ALP is comprised, targeting the peptide-based proteasomal degradation system would be a good alternative. In this study, we designed a fusion peptide containing an α-syn-binding domain and a short strong proteasome-targeting motif. Read More

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http://dx.doi.org/10.1016/j.chembiol.2020.03.010DOI Listing

Inhibition of Resistance-Refractory P. falciparum Kinase PKG Delivers Prophylactic, Blood Stage, and Transmission-Blocking Antiplasmodial Activity.

Cell Chem Biol 2020 Apr 16. Epub 2020 Apr 16.

Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY 10032, USA; Division of Infectious Diseases, Columbia University Irving Medical Center, New York, NY 10032, USA. Electronic address:

The search for antimalarial chemotypes with modes of action unrelated to existing drugs has intensified with the recent failure of first-line therapies across Southeast Asia. Here, we show that the trisubstituted imidazole MMV030084 potently inhibits hepatocyte invasion by Plasmodium sporozoites, merozoite egress from asexual blood stage schizonts, and male gamete exflagellation. Metabolomic, phosphoproteomic, and chemoproteomic studies, validated with conditional knockdown parasites, molecular docking, and recombinant kinase assays, identified cGMP-dependent protein kinase (PKG) as the primary target of MMV030084. Read More

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http://dx.doi.org/10.1016/j.chembiol.2020.04.001DOI Listing

Plasmodium vivax Liver and Blood Stages Recruit the Druggable Host Membrane Channel Aquaporin-3.

Cell Chem Biol 2020 Jun 23;27(6):719-727.e5. Epub 2020 Apr 23.

Department of Molecular Genetics and Microbiology, Duke University Medical Center, 213 Research Drive, Durham, NC 27710, USA; Chemistry Department, Duke University, 124 Science Drive, Durham, NC 27708, USA. Electronic address:

Plasmodium vivax infects hepatocytes to form schizonts that cause blood infection, or dormant hypnozoites that can persist for months in the liver before leading to relapsing blood infections. The molecular processes that drive P. vivax schizont and hypnozoite survival remain largely unknown, but they likely involve a rich network of host-pathogen interactions, including those occurring at the host-parasite interface, the parasitophorous vacuole membrane (PVM). Read More

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http://dx.doi.org/10.1016/j.chembiol.2020.03.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303948PMC

Combined Omics Approach Identifies Gambogic Acid and Related Xanthones as Covalent Inhibitors of the Serine Palmitoyltransferase Complex.

Cell Chem Biol 2020 May 23;27(5):586-597.e12. Epub 2020 Apr 23.

Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA. Electronic address:

In this study, we identify the natural product gambogic acid as well as structurally related synthetic xanthones as first-in-class covalent inhibitors of the de novo sphingolipid biosynthesis. We apply chemoproteomics to determine that gambogic acid binds to the regulatory small subunit B of the serine palmitoyltransferase complex (SPTSSB). We then test structurally related synthetic xanthones to identify 18 as an equally potent but more selective binder of SPTSSB and show that 18 reduces sphingolipid levels in situ and in vivo. Read More

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http://dx.doi.org/10.1016/j.chembiol.2020.03.008DOI Listing

Simultaneous Control of Endogenous and User-Defined Genetic Pathways Using Unique ecDHFR Pharmacological Chaperones.

Cell Chem Biol 2020 May 23;27(5):622-634.e6. Epub 2020 Apr 23.

Department of Ophthalmology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, USA; Department of Pharmacology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, USA. Electronic address:

Destabilizing domains (DDs), such as a mutated form of Escherichia coli dihydrofolate reductase (ecDHFR), confer instability and promote protein degradation. However, when combined with small-molecule stabilizers (e.g. Read More

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http://dx.doi.org/10.1016/j.chembiol.2020.03.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7245562PMC

Progress in Understanding Ferroptosis and Challenges in Its Targeting for Therapeutic Benefit.

Cell Chem Biol 2020 Apr;27(4):463-471

Chemical Biology and Therapeutics Science Program, Broad Institute, Cambridge, MA 02142, USA; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA. Electronic address:

Ferroptosis is an iron-dependent cell-death modality driven by oxidative phospholipid damage. In contrast to apoptosis, which enables organisms to eliminate targeted cells purposefully at specific times, ferroptosis appears to be a vulnerability of cells that otherwise use high levels of polyunsaturated lipids to their advantage. Cells in this high polyunsaturated lipid state generally have safeguards that mitigate ferroptotic risk. Read More

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http://dx.doi.org/10.1016/j.chembiol.2020.03.015DOI Listing

Ferroptosis and Necroptosis in the Kidney.

Cell Chem Biol 2020 Apr;27(4):448-462

Division of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Fletscherstrasse 74, 01307, Dresden, Germany. Electronic address:

In the last decade, the role of apoptosis in the pathophysiology of acute kidney injury (AKI) and AKI to chronic kidney disease (CKD) progression has been revisited as our understanding of ferroptosis and necroptosis has emerged. A growing body of evidence, reviewed here, ascribes a central pathophysiological role for ferroptosis and necroptosis to AKI, nephron loss, and acute tubular necrosis. We will introduce concepts to the non-cell-autonomous manner of kidney tubular injury during ferroptosis, a phenomenon that we refer to as a "wave of death. Read More

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http://dx.doi.org/10.1016/j.chembiol.2020.03.016DOI Listing

The Chemistry and Biology of Ferroptosis.

Cell Chem Biol 2020 Apr;27(4):365-375

Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address:

Ferroptosis is a recently described form of cell death driven by iron-dependent lipid peroxidation. This type of cell death was first observed in response to treatment of tumor cells with a small-molecule chemical probe named erastin. Most subsequent advances in understanding the mechanisms governing ferroptosis involved the use of genetic screens and small-molecule probes. Read More

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http://dx.doi.org/10.1016/j.chembiol.2020.03.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7204503PMC

Selenium: Tracing Another Essential Element of Ferroptotic Cell Death.

Cell Chem Biol 2020 Apr 9;27(4):409-419. Epub 2020 Apr 9.

Institute of Metabolism and Cell Death, Helmholtz Zentrum München, 85764 Neuherberg, Germany.

The trace elements iron and selenium play decisive roles in a distinct form of necrotic cell death, known as ferroptosis. While iron promotes ferroptosis by contributing to Fenton-type reactions and uncontrolled lipid autoxidation, the hallmark of ferroptosis, selenium in the form of glutathione peroxidase 4 (GPX4), subdues phospholipid peroxidation and associated cell death. Beyond the canonical cystine/glutamate antiporter system x/glutathione/GPX4 nexus, recent studies unveiled the second mainstay in ferroptosis entailing extra-mitochondrial ubiquinone, ferroptosis suppressor protein 1, and NAD(P)H as electron donor. Read More

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http://dx.doi.org/10.1016/j.chembiol.2020.03.012DOI Listing

Achieving Life through Death: Redox Biology of Lipid Peroxidation in Ferroptosis.

Cell Chem Biol 2020 Apr 9;27(4):387-408. Epub 2020 Apr 9.

Children's Neuroscience Institute, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA 15224, USA; Center for Free Radical and Antioxidant Health, Department of Environmental Health, University of Pittsburgh, Pittsburgh, PA 15213, USA; Institute for Regenerative Medicine, Sechenov First Moscow State Medical University, 119991 Moscow, Russia. Electronic address:

Redox balance is essential for normal brain, hence dis-coordinated oxidative reactions leading to neuronal death, including programs of regulated death, are commonly viewed as an inevitable pathogenic penalty for acute neuro-injury and neurodegenerative diseases. Ferroptosis is one of these programs triggered by dyshomeostasis of three metabolic pillars: iron, thiols, and polyunsaturated phospholipids. This review focuses on: (1) lipid peroxidation (LPO) as the major instrument of cell demise, (2) iron as its catalytic mechanism, and (3) thiols as regulators of pro-ferroptotic signals, hydroperoxy lipids. Read More

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http://dx.doi.org/10.1016/j.chembiol.2020.03.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7218794PMC

Breakdown of an Ironclad Defense System: The Critical Role of NRF2 in Mediating Ferroptosis.

Cell Chem Biol 2020 Apr 9;27(4):436-447. Epub 2020 Apr 9.

Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, 1703 East Mabel Street, Tucson, AZ 85721, USA; University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, USA. Electronic address:

Ferroptosis is a non-apoptotic mode of regulated cell death that is iron and lipid peroxidation dependent. As new mechanistic insight into ferroptotic effectors and how they are regulated in different disease contexts is uncovered, our understanding of the physiological and pathological relevance of this mode of cell death continues to grow. Along these lines, a host of pharmacological modulators of this pathway have been identified, targeting proteins involved in iron homeostasis; the generation and reduction of lipid peroxides; or cystine import and glutathione metabolism. Read More

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http://dx.doi.org/10.1016/j.chembiol.2020.03.011DOI Listing

Cellular Stress Upregulates Indole Signaling Metabolites in Escherichia coli.

Cell Chem Biol 2020 Jun 2;27(6):698-707.e7. Epub 2020 Apr 2.

Department of Chemistry, Yale University, New Haven, CT 06520, USA; Chemical Biology Institute, Yale University, West Haven, CT 06516, USA; Department of Microbial Pathogenesis, Yale School of Medicine, New Haven, CT 06536, USA. Electronic address:

Escherichia coli broadly colonize the intestinal tract of humans and produce a variety of small molecule signals. However, many of these small molecules remain unknown. Here, we describe a family of widely distributed bacterial metabolites termed the "indolokines. Read More

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http://dx.doi.org/10.1016/j.chembiol.2020.03.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7306003PMC

The Chemical Biology of Ferroptosis in the Central Nervous System.

Authors:
Rajiv R Ratan

Cell Chem Biol 2020 May 2;27(5):479-498. Epub 2020 Apr 2.

Burke Neurological Institute at Weill Cornell Medicine, 785 Mamaroneck Avenue, White Plains, NY 10605, USA. Electronic address:

Over the past five decades, thanatology has come to include the study of how individual cells in our bodies die appropriately and inappropriately in response to physiological and pathological stimuli. Morphological and biochemical criteria have been painstakingly established to create clarity around definitions of distinct types of cell death and mechanisms for their activation. Among these, ferroptosis has emerged as a unique, oxidative stress-induced cell death pathway with implications for diseases as diverse as traumatic brain injury, hemorrhagic stroke, Alzheimer's disease, cancer, renal ischemia, and heat stress in plants. Read More

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http://dx.doi.org/10.1016/j.chembiol.2020.03.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7245561PMC

Site-Specific Photo-Crosslinking Proteomics Reveal Regulation of IFITM3 Trafficking and Turnover by VCP/p97 ATPase.

Cell Chem Biol 2020 May 2;27(5):571-585.e6. Epub 2020 Apr 2.

State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen 518055, China. Electronic address:

Interferon-induced transmembrane protein 3 (IFITM3) is a key interferon effector that broadly prevents infection by diverse viruses. However, the cellular factors that control IFITM3 homeostasis and antiviral activity have not been fully elucidated. Using site-specific photo-crosslinking and quantitative proteomic analysis, here we present the identification and functional characterization of VCP/p97 AAA-ATPase as a primary interaction partner of IFITM3. Read More

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http://dx.doi.org/10.1016/j.chembiol.2020.03.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7194980PMC

Polypharmacological Perturbation of the 14-3-3 Adaptor Protein Interactome Stimulates Neurite Outgrowth.

Cell Chem Biol 2020 Jun 26;27(6):657-667.e6. Epub 2020 Mar 26.

Department of Neurology and Neurosurgery, Montréal Neurological Institute, McGill University, Montréal, QC, Canada. Electronic address:

Targeting protein-protein interactions (PPIs) is a promising approach in the development of drugs for many indications. 14-3-3 proteins are a family of phosphoprotein-binding molecules with critical functions in dozens of cell signaling networks. 14-3-3s are abundant in the central nervous system, and the small molecule fusicoccin-A (FC-A), a tool compound that can be used to manipulate 14-3-3 PPIs, enhances neurite outgrowth in cultured neurons. Read More

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http://dx.doi.org/10.1016/j.chembiol.2020.02.010DOI Listing

Investigating Nonapoptotic Cell Death Using Chemical Biology Approaches.

Cell Chem Biol 2020 Apr 26;27(4):376-386. Epub 2020 Mar 26.

Department of Biology, Stanford University, Stanford, CA 94305, USA. Electronic address:

Nonapoptotic cell death is important for human health and disease. Here, we show how various tools and techniques drawn from the chemical biology field have played a central role in the discovery and characterization of nonapoptotic cell death pathways. Focusing on the example of ferroptosis, we describe how phenotypic screening, chemoproteomics, chemical genetic analysis, and other methods enabled the elucidation of this pathway. Read More

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http://dx.doi.org/10.1016/j.chembiol.2020.03.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7185180PMC

Development of Potent, Selective Surrogate WNT Molecules and Their Application in Defining Frizzled Requirements.

Cell Chem Biol 2020 May 26;27(5):598-609.e4. Epub 2020 Mar 26.

Surrozen Inc., 171 Oyster Point Boulevard, Suite 400, South San Francisco, CA 94080, USA. Electronic address:

WNTs regulate myriad biological processes during embryonic development and are key regulators of stem cell function, tissue homeostasis, and injury repair in adults. The creation of WNT-based therapies has been hampered by challenges in developing soluble, potent, and selective WNT molecules. Soluble WNT surrogates have been reported, but they demonstrate relatively weak WNT signaling activity. Read More

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http://dx.doi.org/10.1016/j.chembiol.2020.02.009DOI Listing

Hunting Cells for Gentle Liberation.

Cell Chem Biol 2020 Mar;27(3):257-258

Life and Medical Sciences Institute, University of Bonn, Gerhard-Domagk-Str. 1, 53121 Bonn, Germany; Center of Aptamer Research and Development, University of Bonn, Gerhard-Domagk-Str. 1, 53121 Bonn, Germany.

In a recent issue of Cell Chemical Biology, Gray et al. (2020) report an aptamer-based method to reversibly label and isolate EGF receptor-expressing cells from heterogeneous mixtures by cell sorting approaches. Subsequent treatment using complementary oligonucleotides restores full functionality of EGF receptors, highlighting the superiority of this method to antibody-based sorting. Read More

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http://dx.doi.org/10.1016/j.chembiol.2020.02.006DOI Listing

New Spins on Old Drugs: Enhancing Activity of Antifungals.

Cell Chem Biol 2020 Mar;27(3):255-256

Department of Medicine, Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27701, USA. Electronic address:

In this issue of Cell Chemical Biology, Caplan et al. (2020) describe a series of studies in the human fungal pathogen Candida albicans to identify a new target for antimicrobial drug development. Beginning with an unbiased compound screen, they identify new mechanisms to address rising resistance to currently used anti-infective agents. Read More

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http://dx.doi.org/10.1016/j.chembiol.2020.03.001DOI Listing

A Promising CPS1 Inhibitor Keeping Ammonia from Fueling Cancer.

Cell Chem Biol 2020 Mar;27(3):253-254

Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.

Carbamoyl phosphate synthetase 1 (CPS1) drives ammonia conversion to carbamoyl phosphate, and its overexpression supports pyrimidine synthesis and tumor growth, highlighting the potential of CPS1 inhibition as a therapeutic target. In this issue of Cell Chemical Biology, Yao et al. (2020) introduce H3B-120 as a promising novel inhibitor of CPS1. Read More

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http://dx.doi.org/10.1016/j.chembiol.2020.03.002DOI Listing

A Preclinical Candidate Targeting Mycobacterium tuberculosis KasA.

Cell Chem Biol 2020 May 19;27(5):560-570.e10. Epub 2020 Mar 19.

Department of Pharmacology, Physiology, and Neuroscience, Rutgers University - New Jersey Medical School, Newark, NJ, USA; Division of Infectious Disease, Department of Medicine and the Ruy V. Lourenco Center for the Study of Emerging and Re-emerging Pathogens, Rutgers University - New Jersey Medical School, Newark, NJ, USA. Electronic address:

Published Mycobacterium tuberculosis β-ketoacyl-ACP synthase KasA inhibitors lack sufficient potency and/or pharmacokinetic properties. A structure-based approach was used to optimize existing KasA inhibitor DG167. This afforded indazole JSF-3285 with a 30-fold increase in mouse plasma exposure. Read More

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http://dx.doi.org/10.1016/j.chembiol.2020.02.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7245553PMC