3,577 results match your criteria ACS chemical biology[Journal]


Genetic and biochemical reconstitution of bromoform biosynthesis in Asparagopsis lends insights into seaweed ROS enzymology.

ACS Chem Biol 2020 May 26. Epub 2020 May 26.

Marine macroalgae, seaweeds, are exceptionally prolific producers of halogenated natural products. Biosynthesis of halogenated molecules in seaweeds is inextricably linked to reactive oxygen species (ROS) signaling as hydrogen peroxide serves as a substrate for haloperoxidase enzymes that participate in the construction these halogenated molecules. Here, using red macroalga Asparagopsis taxiformis, a prolific producer of ozone depleting molecule- bromoform, we provide the discovery and biochemical characterization of a ROS-producing NAD(P)H oxidase from seaweeds. Read More

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http://dx.doi.org/10.1021/acschembio.0c00299DOI Listing

NMT as a glycine and lysine myristoyltransferase in cancer, immunity, and infections.

ACS Chem Biol 2020 May 26. Epub 2020 May 26.

Protein myristoylation, the addition of a 14-carbon saturated acyl group, is an abundant modification implicated in biological events as diverse as development, immunity, oncogenesis, and infections. N-myristoyltransferase (NMT) is the enzyme that catalyzes this modification. Many elegant studies have established the rules guiding the catalysis including substrate amino acid sequence requirement with the indispensable N-terminal glycine, and a co-translational mode of action. Read More

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http://dx.doi.org/10.1021/acschembio.0c00314DOI Listing

Cooperativity Between Orthosteric Inhibitors and Allosteric Inhibitor 8-Anilino-1-Naphthalene Sulfonic Acid (ANS) in Cyclin-Dependent Kinase 2.

ACS Chem Biol 2020 May 20. Epub 2020 May 20.

Institute for Therapeutics Discovery and Development, Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota 55414, United States.

While kinases have been attractive targets to combat many diseases, including cancer, selective kinase inhibition has been challenging, because of the high degree of structural homology in the active site, where many kinase inhibitors bind. We have previously discovered that 8-anilino-1-naphthalene sulfonic acid (ANS) binds an allosteric pocket in cyclin-dependent kinase 2 (Cdk2). Here, we detail the positive cooperativity between ANS and orthosteric Cdk2 inhibitors dinaciclib and roscovitine, which increase the affinity of ANS toward Cdk2 5-fold to 10-fold, and the relatively noncooperative effects of ATP. Read More

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http://dx.doi.org/10.1021/acschembio.0c00169DOI Listing

Small Molecule Channels Harness Membrane Potential to Concentrate Potassium in trk1Δtrk2Δ Yeast.

ACS Chem Biol 2020 May 19. Epub 2020 May 19.

Many protein ion channels harness membrane potential to move ions in opposition to their chemical gradient. Deficiencies of such proteins cause several human diseases, including cystic fibrosis, Bartter Syndrome, and proximal renal tubular acidosis. Using yeast as a eukaryotic model system, we asked whether, in the context of a protein ion channel deficiency in vivo, small molecule channels could similarly harness membrane potential to concentrate ions. Read More

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http://dx.doi.org/10.1021/acschembio.0c00180DOI Listing

Structure-Guided Optimization of Inhibitors of Acetyltransferase Eis from .

ACS Chem Biol 2020 May 18. Epub 2020 May 18.

Department of Pharmaceutical Sciences, University of Kentucky, Lexington, Kentucky 40536-0596, United States.

The enhanced intracellular survival (Eis) protein of () is a versatile acetyltransferase that multiacetylates aminoglycoside antibiotics abolishing their binding to the bacterial ribosome. When overexpressed as a result of promoter mutations, Eis causes drug resistance. In an attempt to overcome the Eis-mediated kanamycin resistance of , we designed and optimized structurally unique thieno[2,3-]pyrimidine Eis inhibitors toward effective kanamycin adjuvant combination therapy. Read More

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http://dx.doi.org/10.1021/acschembio.0c00184DOI Listing

Validating STAT Protein-inhibitor Interactions using Biochemical and Cellular Thermal Shift Assays.

ACS Chem Biol 2020 May 15. Epub 2020 May 15.

Signal transducer and activator of transcription (STAT) proteins have important biological functions, however, deregulation of STAT signaling is a driving force behind the onset and progression of inflammatory diseases and cancer. While their biological roles suggest that STAT proteins would be valuable targets for developing therapeutic agents, STATs are notoriously difficult to inhibit using small drug-like molecules as they do not have a distinct inhibitor binding site. Despite this, a multitude of small molecule STAT inhibitors have been proposed, primarily focusing on inhibiting STAT3 protein to generate novel cancer therapies. Read More

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http://dx.doi.org/10.1021/acschembio.0c00046DOI Listing

Advancing Chemical Microbiology.

ACS Chem Biol 2020 May;15(5):1115-1118

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http://dx.doi.org/10.1021/acschembio.0c00330DOI Listing

A CRISPR-based Screen Links an Inhibitor of Nonsense-mediated Decay to eIF4A3 Target Engagement.

ACS Chem Biol 2020 May 13. Epub 2020 May 13.

Eukaryotic initiation factor (eIF) 4A3 is a DEAD-box RNA helicase and a core component of the exon-junction complex (EJC). The EJC marks the location of exon:exon junctions following the removal of introns by splicing and plays a critical role in an mRNA surveillance program known as nonsense-mediated decay (NMD). NMD is often triggered by the presence of a premature termination codon (PTC) upstream of the EJC, leading to degradation of the variant mRNA which prevents synthesis of a potentially harmful, truncated polypeptide. Read More

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http://dx.doi.org/10.1021/acschembio.0c00253DOI Listing

An aptamer-T cell targeted therapy for tumor treatment using sugar metabolism and click chemistry.

ACS Chem Biol 2020 May 13. Epub 2020 May 13.

The development of a tumor-targeted immunotherapy is highly required. The most advanced application is the use of CD19 chimeric antigen receptor (CAR) T (CAR-T) cells to B-cell malignancies, but there are still side effects including potential carcinogenicity of lentiviral or retroviral insertion into the host cell genome. Here we developed a non-viral aptamer-T-cell targeted strategy for tumor therapy. Read More

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http://dx.doi.org/10.1021/acschembio.0c00164DOI Listing

Impact of Extracellular Fatty Acids and Oxygen Tension on Lipid Synthesis and Assembly in Pancreatic Cancer Cells.

ACS Chem Biol 2020 May 26. Epub 2020 May 26.

Merck & Co., Inc, 213 East Grand Avenue, South San Francisco, California 94080, United States.

Lipid oxidation and biosynthesis are crucial for cell survival, especially for rapidly proliferating cancer cells in a heterogeneous metabolic environment. The storage of high-energy lipid reservoirs competitively advantages the cancer cell over non-neoplastic tissue. Disrupting lipid biosynthetic processes, through modulation of fatty acid (FA) esterification or lipogenesis (DNL), is of interest in drug discovery. Read More

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http://dx.doi.org/10.1021/acschembio.0c00219DOI Listing

Potential G-Quadruplex Forming Sequences and -Methyladenosine Colocalize at Human Pre-mRNA Intron Splice Sites.

ACS Chem Biol 2020 May 26. Epub 2020 May 26.

Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City, Utah 84112-0850, United States.

Maturation of mRNA in humans involves modifying the 5' and 3' ends, splicing introns, and installing epitranscriptomic modifications that are essential for mRNA biogenesis. With respect to epitranscriptomic modifications, they are usually installed in specific consensus motifs, although not all sequences are modified suggesting a secondary structural component to site selection. Using bioinformatic analysis of published data, we identify in human mature-mRNA that potential RNA G-quadruplex (rG4) sequences colocalize with the epitranscriptomic modifications -methyladenosine (mA), pseudouridine (Ψ), and inosine (I). Read More

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http://dx.doi.org/10.1021/acschembio.0c00260DOI Listing

Direct Binding of Salicylic Acid to -Acyl-Homoserine Lactone Synthase.

ACS Chem Biol 2020 May 22. Epub 2020 May 22.

Department of Chemistry, Bar-Ilan University, Ramat-Gan 5290002, Israel.

Salicylic acid (SA) is a hormone that mediates systemic acquired resistance in plants. We demonstrated that SA can interfere with group behavior and virulence of the soft-rot plant pathogen spp. through quorum sensing (QS) inhibition. Read More

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http://dx.doi.org/10.1021/acschembio.0c00185DOI Listing

Discovery and Characterization of Peptide Inhibitors for Calcium and Integrin Binding Protein 1.

ACS Chem Biol 2020 May 26. Epub 2020 May 26.

Center for Integrative Chemical Biology and Drug Discovery, Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, United States.

Calcium and integrin binding protein 1 (CIB1) is an EF-hand-containing, small intracellular protein that has recently been implicated in cancer cell survival and proliferation. In particular, CIB1 depletion significantly impairs tumor growth in triple-negative breast cancer (TNBC). Thus, CIB1 is a potentially attractive target for cancer chemotherapy that has yet to be validated by a chemical probe. Read More

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http://dx.doi.org/10.1021/acschembio.0c00144DOI Listing

Peptide Probes for MyoA Tail Interacting Protein (MTIP): Exploring the Druggability of the Malaria Parasite Motor Complex.

ACS Chem Biol 2020 May 13. Epub 2020 May 13.

Department of Life Sciences, Imperial College, London SW7 2AZ, United Kingdom.

Malaria remains an endemic tropical disease, and the emergence of parasites resistant to current front-line medicines means that new therapeutic targets are required. The glideosome is a multiprotein complex thought to be essential for efficient host red blood cell invasion. At its core is a myosin motor, Myosin A (MyoA), which provides most of the force required for parasite invasion. Read More

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http://dx.doi.org/10.1021/acschembio.0c00328DOI Listing

When the Others Become Us: A Chemist's Perspective of the COVID-19 Outbreak in Italy.

ACS Chem Biol 2020 May 8. Epub 2020 May 8.

Chemistry Department, Università degli Studi di Milano, Milan 20133, Italy.

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http://dx.doi.org/10.1021/acschembio.0c00289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7216762PMC

Covalent Targeting of Ras G12C by Rationally Designed Peptidomimetics.

ACS Chem Biol 2020 May 21. Epub 2020 May 21.

Department of Chemistry, New York University, New York, New York 10003, United States.

Protein-protein interactions (PPIs) play a critical role in fundamental biological processes. Competitive inhibition of these interfaces requires compounds that can access discontinuous binding epitopes along a large, shallow binding surface area. Conformationally defined protein surface mimics present a viable route to target these interactions. Read More

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http://dx.doi.org/10.1021/acschembio.0c00204DOI Listing

Light-Driven Activation of RNA-Guided Nucleic Acid Cleavage.

ACS Chem Biol 2020 May 7. Epub 2020 May 7.

College of Chemistry and Molecular Sciences, Sauvage Center for Molecular Sciences, Key Laboratory of Biomedical Polymers of Ministry of Education, Institute of Advanced Studies, Wuhan University, Wuhan 430072, China.

As one of the most favorable stimuli, photoactivation provides an advantageous way to manipulate biological objects. In the current study, we have successfully demonstrated the use of light activation guide RNA (gRNA) strategy for controlling CRISPR systems. By conjugating photolabile protecting groups, the CRISPR functions became minimal, but exposure of acylated gRNAs to 365 nm light triggers the removal of masking groups, leading to the rescue of CRISPR functions. Read More

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http://dx.doi.org/10.1021/acschembio.0c00105DOI Listing
May 2020
5.331 Impact Factor

Discovery and SAR of Natural-Product-Inspired RXR Agonists with Heterodimer Selectivity to PPARδ-RXR.

ACS Chem Biol 2020 May 6. Epub 2020 May 6.

Laboratory of Medicinal Resources, School of Pharmacy, Aichi Gakuin University, 1-100 Kusumoto-cho, Chikusa-ku, Nagoya 464-8650, Japan.

A known natural product, magnaldehyde B, was identified as an agonist of retinoid X receptor (RXR) α. Magnaldehyde B was isolated from (Magnoliaceae) and synthesized along with more potent analogs for screening of their RXRα agonistic activities. Structural optimization of magnaldehyde B resulted in the development of a candidate molecule that displayed a 440-fold increase in potency. Read More

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http://dx.doi.org/10.1021/acschembio.0c00146DOI Listing

Chemical Inhibitors of a Selective SWI/SNF Function Synergize with ATR Inhibition in Cancer Cell Killing.

ACS Chem Biol 2020 May 5. Epub 2020 May 5.

SWI/SNF (BAF) complexes are a diverse family of ATP-dependent chromatin remodelers produced by combinatorial assembly that are mutated in and thought to contribute to 20% of human cancers and a large number of neurologic diseases. The gene-activating functions of BAF complexes are essential for viability of many cell types, limiting the development of small molecule inhibitors. To circumvent the potential toxicity of SWI/SNF inhibition, we identified small molecules that inhibit the specific repressive function of these complexes but are relatively non-toxic and importantly synergize with ATR inhibitors in killing cancer cells. Read More

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http://dx.doi.org/10.1021/acschembio.0c00312DOI Listing

Local Stabilization of Subunit-Subunit Contacts Causes Global Destabilization of Hepatitis B Virus Capsids.

ACS Chem Biol 2020 May 19. Epub 2020 May 19.

Molecular and Cellular Biology Department, Indiana University-Bloomington, Bloomington, Indiana 47401, United States.

Development of antiviral molecules that bind virion is a strategy that remains in its infancy, and the details of their mechanisms are poorly understood. Here we investigate the behavior of DBT1, a dibenzothiazepine that specifically interacts with the capsid protein of hepatitis B virus (HBV). We found that DBT1 stabilizes protein-protein interaction, accelerates capsid assembly, and can induce formation of aberrant particles. Read More

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http://dx.doi.org/10.1021/acschembio.0c00320DOI Listing

Direct Sequencing of tRNA by 2D-HELS-AA MS Seq Reveals Its Different Isoforms and Dynamic Base Modifications.

ACS Chem Biol 2020 May 19. Epub 2020 May 19.

Department of Biological and Chemical Sciences, New York Institute of Technology, New York, New York 10023, United States.

Post-transcriptional modifications are intrinsic to RNA structure and function. However, methods to sequence RNA typically require a cDNA intermediate and are either not able to sequence these modifications or are tailored to sequence one specific nucleotide modification only. Interestingly, some of these modifications occur with <100% frequency at their particular sites, and site-specific quantification of their stoichiometries is another challenge. Read More

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http://dx.doi.org/10.1021/acschembio.0c00119DOI Listing

Analysis of Amylin Consensus Sequences Suggests that Human Amylin is Not Optimized to Minimize Amyloid Formation and Provides Clues to Factors that Modulate Amyloidogenicity.

ACS Chem Biol 2020 May 4. Epub 2020 May 4.

The neuropancreatic polypeptide hormone amylin forms pancreatic islet amyloid in type-2 diabetes. Islet amyloid formation contributes to β-cell death in the disease and to the failure of islet transplants, but the features which influence amylin amyloidogenicity are not understood. We constructed an amino acid sequence alignment of 202 sequences of amylin and used the alignment to design consensus sequences of vertebrate amylins, mammalian amylins, and primate amylins. Read More

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http://dx.doi.org/10.1021/acschembio.9b01050DOI Listing

Solid-Phase Peptide Capture and Release for Bulk and Single-Molecule Proteomics.

ACS Chem Biol 2020 May 14. Epub 2020 May 14.

Department of Chemistry, University of Texas at Austin, 100 E. 24th Street, Austin, Texas 78712, United States.

The field of proteomics has expanded recently with more sensitive techniques for the bulk measurement of peptides as well as single-molecule techniques. One limiting factor for some of these methods is the need for multiple chemical derivatizations and highly pure proteins free of contaminants. We demonstrate a solid-phase capture-release strategy suitable for the proteolysis, purification, and subsequent chemical modification of peptides. Read More

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http://dx.doi.org/10.1021/acschembio.0c00040DOI Listing

Structure-Guided Biochemical Analysis of Quorum Signal Synthase Specificities.

ACS Chem Biol 2020 May 13. Epub 2020 May 13.

Department of Chemistry and Biochemistry, Boise State University, Boise, Idaho, United States.

Many bacteria use membrane-diffusible small molecule quorum signals to coordinate gene transcription in response to changes in cell density, known as quorum sensing (QS). Among these, acyl-homoserine lactones (AHL) are widely distributed in and are involved in controlling the expression of virulence genes and biofilm formation in pathogens, such as . AHL molecules are specifically biosynthesized by the cognate LuxI type AHL synthases using -adenosylmethionine (SAM) and either acyl carrier protein (ACP)- or CoA-coupled fatty acids through a two-step reaction. Read More

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http://dx.doi.org/10.1021/acschembio.0c00142DOI Listing

Discovery and Characterization of a Class IV Lanthipeptide with a Nonoverlapping Ring Pattern.

ACS Chem Biol 2020 May 14. Epub 2020 May 14.

Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States.

Lanthipeptides constitute a major family of ribosomally synthesized and post-translationally modified peptides (RiPPs). They are classified into four subfamilies, based on the characteristics of their lanthipeptide synthetases. While over a hundred lanthipeptides have been discovered to date, very few of them are class IV lanthipeptides and the latter are all structurally similar. Read More

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http://dx.doi.org/10.1021/acschembio.0c00267DOI Listing

Dual Neutral Sphingomyelinase-2/Acetylcholinesterase Inhibitors for the Treatment of Alzheimer's Disease.

ACS Chem Biol 2020 May 14. Epub 2020 May 14.

Drug Discovery Laboratory, Department of Neurology, Mary S. Easton Center for Alzheimer's Disease Research, University of California, Los Angeles, California 90095, United States.

We report the discovery of a novel class of compounds that function as dual inhibitors of the enzymes neutral sphingomyelinase-2 (nSMase2) and acetylcholinesterase (AChE). Inhibition of these enzymes provides a unique strategy to suppress the propagation of tau pathology in the treatment of Alzheimer's disease (AD). We describe the key SAR elements that affect relative nSMase2 and/or AChE inhibitor effects and potency, in addition to the identification of two analogs that suppress the release of tau-bearing exosomes and . Read More

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http://dx.doi.org/10.1021/acschembio.0c00311DOI Listing

mRNA Display Discovery of a Novel Programmed Death Ligand 1 (PD-L1) Binding Peptide (a Peptide Ligand for PD-L1).

ACS Chem Biol 2020 Apr 30. Epub 2020 Apr 30.

Department of Chemistry, University of Southern California, Los Angeles, California 90089, United States.

Programmed death ligand 1 (PD-L1) is a critical immune checkpoint ligand whose overexpression on tumor cells provides a mechanism of escape from immune surveillance. The interaction between PD-L1 and PD-1 on T cell lymphocytes suppresses both T cell activation and effector function and is engaged by cancers to dampen antitumor immunity. Here, we used mRNA display to engineer an 18-residue linear peptide that binds to human PD-L1. Read More

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http://dx.doi.org/10.1021/acschembio.0c00264DOI Listing

Hydrocarbon-stitched Peptide Agonists of Glucagon-Like Peptide-1 Receptor.

ACS Chem Biol 2020 Apr 29. Epub 2020 Apr 29.

Glucagon-like peptide 1 (GLP-1) is a natural peptide agonist of the GLP-1 receptor (GLP-1R) found on pancreatic β-cells. Engagement of the receptor stimulates insulin release in a glucose-dependent fashion and increases β-cell mass, two ideal features for pharmacologic management of type 2 diabetes. Thus, intensive efforts have focused on developing GLP-1-based peptide agonists of GLP-1R for therapeutic application. Read More

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http://dx.doi.org/10.1021/acschembio.0c00308DOI Listing

Targeting Cancer Gene Dependencies with Anthrax-Mediated Delivery of Peptide Nucleic Acids.

ACS Chem Biol 2020 May 11. Epub 2020 May 11.

Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.

Antisense oligonucleotide therapies are important cancer treatments, which can suppress genes in cancer cells that are critical for cell survival. has recently emerged as a promising gene target that encodes a key splicing factor in the SF3B protein complex. Over 10% of cancers have lost one or more copies of the gene, rendering these cancers vulnerable after further suppression. Read More

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http://dx.doi.org/10.1021/acschembio.9b01027DOI Listing

A Light-Inducible Hedgehog Signaling Activator Modulates Proliferation and Differentiation of Neural Cells.

ACS Chem Biol 2020 May 11. Epub 2020 May 11.

The Hedgehog signaling pathway shapes our body by regulating the proliferation and differentiation of cells. The spatial and temporal distribution pattern of its ligands finely controls the activity of the Hedgehog pathway during development. To model the control of Hedgehog signaling activities in vitro, we developed a light-inducible Hedgehog signaling activator 6-nitroveratryloxy-carbonyl Smoothened agonist (NVOC-SAG). Read More

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http://dx.doi.org/10.1021/acschembio.0c00195DOI Listing

Antibody-PROTAC Conjugates Enable HER2-Dependent Targeted Protein Degradation of BRD4.

ACS Chem Biol 2020 Apr 30. Epub 2020 Apr 30.

Department of Chemistry, Imperial College London, Molecular Sciences Research Hub, 80 Wood Lane, London, W12 0BZ, United Kingdom.

Targeting protein degradation with Proteolysis-Targeting Chimeras (PROTACs) is an area of great current interest in drug discovery. Nevertheless, although the high effectiveness of PROTACs against a wide variety of targets has been established, most degraders reported to date display limited intrinsic tissue selectivity and do not discriminate between cells of different types. Here, we describe a strategy for selective protein degradation in a specific cell type. Read More

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http://dx.doi.org/10.1021/acschembio.0c00285DOI Listing
April 2020
5.331 Impact Factor

Obtusaquinone: A Cysteine-Modifying Compound That Targets Keap1 for Degradation.

ACS Chem Biol 2020 May 8. Epub 2020 May 8.

Experimental Therapeutics and Molecular Imaging Unit, Department of Neurology, Neuro-Oncology Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, United States.

We have previously identified the natural product obtusaquinone (OBT) as a potent antineoplastic agent with promising activity in glioblastoma and breast cancer through the activation of oxidative stress; however, the molecular properties of this compound remained elusive. We used a multidisciplinary approach comprising medicinal chemistry, quantitative mass spectrometry-based proteomics, functional studies in cancer cells, and pharmacokinetic analysis, as well as mouse xenograft models to develop and validate novel OBT analogs and characterize the molecular mechanism of action of OBT. We show here that OBT binds to cysteine residues with a particular affinity to cysteine-rich Keap1, a member of the CUL3 ubiquitin ligase complex. Read More

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http://dx.doi.org/10.1021/acschembio.0c00104DOI Listing

Generation of Recombinant Mammalian Selenoproteins through Genetic Code Expansion with Photocaged Selenocysteine.

ACS Chem Biol 2020 May 5. Epub 2020 May 5.

Department of Chemistry, Boston College, Chestnut Hill, Massachusetts 02467, United States.

Selenoproteins contain the amino acid selenocysteine (Sec) and are found in all domains of life. The functions of many selenoproteins are poorly understood, partly due to difficulties in producing recombinant selenoproteins for cell-biological evaluation. Endogenous mammalian selenoproteins are produced through a noncanonical translation mechanism requiring suppression of the UGA stop codon and a Sec insertion sequence (SECIS) element in the 3' untranslated region of the mRNA. Read More

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http://dx.doi.org/10.1021/acschembio.0c00147DOI Listing

Fr-PPIChem: An Academic Compound Library Dedicated to Protein-Protein Interactions.

ACS Chem Biol 2020 May 5. Epub 2020 May 5.

CRCM, CNRS, INSERM, Institut Paoli-Calmettes, Aix-Marseille Univ, 13009, Marseille, France.

Protein-protein interactions (PPIs) mediate nearly every cellular process and represent attractive targets for modulating disease states but are challenging to target with small molecules. Despite this, several PPI inhibitors (iPPIs) have entered clinical trials, and a growing number of PPIs have become validated drug targets. However, high-throughput screening efforts still endure low hit rates mainly because of the use of unsuitable screening libraries. Read More

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http://dx.doi.org/10.1021/acschembio.0c00179DOI Listing

Cellular Uptake and Cytosolic Delivery of a Cyclic Cystine Knot Scaffold.

ACS Chem Biol 2020 May 6. Epub 2020 May 6.

Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.

Cyclotides are macrocyclic peptides with exceptionally stable structures and have been reported to penetrate cells, making them promising scaffolds for the delivery of inhibitory peptides to target intracellular proteins. However, their cellular uptake and cytosolic localization have been poorly understood until now, which has limited their therapeutic potential. In this study, the recently developed chloroalkane penetration assay was combined with established assays to characterize the cellular uptake and cytosolic delivery of the prototypic cyclotide, kalata B1. Read More

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http://dx.doi.org/10.1021/acschembio.0c00297DOI Listing

Empowering Global Chemical Biology at the Dawn of the New Decade.

ACS Chem Biol 2020 Apr 24. Epub 2020 Apr 24.

Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland.

On January 22-24, 2020, scientific luminaries across the far-flung corners of chemical biology gathered in Geneva, Switzerland, to deliver their latest and greatest discoveries in the field. Generously supported by the Swiss National Science Foundation (SNSF), our academic partners, and industrial and journal sponsors, this chemical biology symposium in our opinion will remain memorable for several years to come, not only because of the diversity in scientific topics delivered by our invited eminent speakers as detailed herein, but it is also one-of-a-kind conference which reflected multidimensional balance-balance in age and gender, across these speakers. Such a remarkable speaker line-up doubtless attracted >200 attendees from academia and industry in and around Switzerland and beyond, representing a huge swathe of subfields of science interfacing chemistry and biology. Read More

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http://dx.doi.org/10.1021/acschembio.0c00135DOI Listing

Isoenzyme-Selective Inhibitors of Human Neuraminidases Reveal Distinct Effects on Cell Migration.

ACS Chem Biol 2020 May 6. Epub 2020 May 6.

Department of Chemistry, University of Alberta, Edmonton, Alberta T6G 2G2, Canada.

The human neuraminidase enzymes (NEU1, NEU2, NEU3, and NEU4) are a class of enzymes implicated in pathologies including cancer and diabetes. Several reports have linked neuraminidase activity to the regulation of cell migration in cancer cells. Using an in vitro cell migration assay on fibronectin (FN) coated surfaces, we have investigated the role of these enzymes in integrin-mediated cell migration. Read More

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http://dx.doi.org/10.1021/acschembio.9b00975DOI Listing

Discovery of Cryptic Largimycins in Reveals Novel Biosynthetic Avenues Enriching the Structural Diversity of the Leinamycin Family.

ACS Chem Biol 2020 Apr 29. Epub 2020 Apr 29.

Departamento de Biología Funcional e Instituto Universitario de Oncología del Principado de Asturias (I.U.O.P.A), Universidad de Oviedo, Oviedo, Spain.

Largimycins are hybrid nonribosomal peptide-polyketides that constitute a new group of metabolites in the leinamycin family of natural products displaying unique structural features such as containing an oxazole instead of a thiazole ring or being oxime ester macrocycles, unprecedented in nature, rather than macrolactams. Their discovery in and has relied on the activation of two homologous silent gene clusters by overexpressing a transcriptional activator and cultivating in specific media. The proposed biosynthesis of largimycins includes the key action of the oxidoreductase LrgO, responsible for the formation of the oxime group involved in macrocyclization, and two putative cryptic biosynthetic steps consisting of chlorination of l-Thr by the NRPS loading module and incorporation of an olefinic exomethylene group by LrgJ PKS. Read More

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http://dx.doi.org/10.1021/acschembio.0c00160DOI Listing

Cyanopyrrolidine Inhibitors of Ubiquitin Specific Protease 7 Mediate Desulfhydration of the Active-Site Cysteine.

ACS Chem Biol 2020 Apr 17. Epub 2020 Apr 17.

Department of Pharmaceutical Chemistry and Small Molecule Discovery Center University of California, San Francisco, California 94143, United States.

Ubiquitin specific protease 7 (USP7) regulates the protein stability of key cellular regulators in pathways ranging from apoptosis to neuronal development, making it a promising therapeutic target. Here we used an engineered, activated variant of the USP7 catalytic domain to perform structure-activity studies of electrophilic peptidomimetic inhibitors. Employing this USP7 variant, we found that inhibitors with a cyanopyrrolidine warhead unexpectedly promoted a β-elimination reaction of the initial covalent adducts, thereby converting the active-site cysteine residue to dehydroalanine. Read More

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http://dx.doi.org/10.1021/acschembio.0c00031DOI Listing

Dual-Activatable Cell Tracker for Controlled and Prolonged Single-Cell Labeling.

ACS Chem Biol 2020 Apr 28. Epub 2020 Apr 28.

Laboratory of Organic Chemistry, ETH Zürich, 8093, Zürich, Switzerland.

Cell trackers are fluorescent chemical tools that facilitate imaging and tracking cells within live organisms. Despite their versatility, these dyes lack specificity, tend to leak outside of the cell, and stain neighboring cells. Here, we report a dual-activatable cell tracker for increased spatial and temporal staining control, especially for single-cell tracking. Read More

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http://dx.doi.org/10.1021/acschembio.0c00208DOI Listing

Substrate Recognition by the Class II Lanthipeptide Synthetase HalM2.

ACS Chem Biol 2020 Apr 28. Epub 2020 Apr 28.

Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States.

Class II lanthipeptides belong to a diverse group of natural products known as ribosomally synthesized and post-translationally modified peptides (RiPPs). Most RiPP precursor peptides contain an N-terminal recognition sequence known as the leader peptide, which is typically recognized by biosynthetic enzymes that catalyze modifications on the C-terminal core peptide. For class II lanthipeptides, these are carried out by a bifunctional lanthipeptide synthetase (LanM) that catalyzes dehydration and cyclization reactions on peptidic substrates to generate thioether-containing, macrocyclic molecules. Read More

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http://dx.doi.org/10.1021/acschembio.0c00127DOI Listing

Asymmetric Total Synthesis of Mycobacterial Diacyl Trehaloses Demonstrates a Role for Lipid Structure in Immunogenicity.

ACS Chem Biol 2020 Apr 24. Epub 2020 Apr 24.

Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 7, 9747 AG Groningen, The Netherlands.

The first asymmetric total synthesis of three structures proposed for mycobacterial diacyl trehaloses, DAT, DAT, and DAT is reported. The presence of two of these glycolipids, DAT and DAT, within different strains of pathogenic M. tuberculosis was confirmed, and it was shown that their abundance varies significantly. Read More

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http://dx.doi.org/10.1021/acschembio.0c00030DOI Listing

RNA Phosphorothioate Modification in Prokaryotes and Eukaryotes.

ACS Chem Biol 2020 Apr 15. Epub 2020 Apr 15.

RNA modifications play important roles in RNA structures and regulation of gene expression and translation. We report the first RNA modification on the phosphate, the RNA phosphorothioate (PS) modification, discovered in both prokaryotes and eukaryotes. The PS modification is also first reported on nucleic acids of eukaryotes. Read More

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http://dx.doi.org/10.1021/acschembio.0c00163DOI Listing

Exploration of Hygromycin B Biosynthesis Utilizing CRISPR-Cas9-Associated Base Editing.

ACS Chem Biol 2020 Apr 22. Epub 2020 Apr 22.

Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, and School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, People's Republic of China.

Hygromycin B is an aminoglycoside antibiotic widely used in industry and biological research. However, most of its biosynthetic pathway has not been completely identified due to the immense difficulty in genetic manipulation of the producing strain. To address this problem, we developed an efficient system that combines clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9-associated base editing and site-specific recombination instead of conventional double-crossover-based homologous recombination. Read More

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http://dx.doi.org/10.1021/acschembio.0c00071DOI Listing

hFUT1-Based Live-Cell Assay To Profile α1-2-Fucoside-Enhanced Influenza Virus A Infection.

ACS Chem Biol 2020 04 9;15(4):819-823. Epub 2020 Apr 9.

Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California 92037, United States.

Host cell surface glycans play critical roles in influenza virus A (IVA) infection ranging from modulation of IVA attachment to membrane fusion and host tropism. Approaches for quick and sensitive profile of viral avidity toward a specific type of host cell glycan can contribute to the understanding of tropism switching among different IVA strains. Here, we developed a method based on chemoenzymatic glycan engineering to investigate the possible involvement of α1-2-fucosides in IVA infections. Read More

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http://dx.doi.org/10.1021/acschembio.9b00869DOI Listing

Two-Stage Strategy for Development of Proteolysis Targeting Chimeras and its Application for Estrogen Receptor Degraders.

ACS Chem Biol 2020 Apr 16. Epub 2020 Apr 16.

School of Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin 53705, United States.

Proteolysis targeting chimeras (PROTACs) have emerged as useful chemical probes and potential therapeutics by taking advantage of the ubiquitin-proteasome system to degrade intracellular disease-associated proteins. PROTACs are heterobifunctional molecules composed of a target protein ligand, E3 ubiquitin ligase ligand, and a linker between them. The generation of efficient PROTACs requires screening of many parameters, especially the lengths and types of the linkers. Read More

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http://dx.doi.org/10.1021/acschembio.0c00140DOI Listing

A Novel Radioligand Reveals Tissue Specific Pharmacological Modulation of Glucocorticoid Receptor Expression with Positron Emission Tomography.

ACS Chem Biol 2020 Apr 15. Epub 2020 Apr 15.

Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California 94158, United States.

The complexity of glucocorticoid receptor (GR) signaling cannot be measured with direct tissue analysis in living subjects, which has stifled our understanding of GR's role in human physiology or disease and impeded the development of selective GR modulators. Herein, we report F-5-(4-fluorobenzyl)-10-methoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-]quinoline (F-YJH08), a radioligand that enables noninvasive measurements of tissue autonomous GR expression levels with positron emission tomography (PET). YJH08 potently binds GR ( ∼ 0. Read More

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http://dx.doi.org/10.1021/acschembio.9b01043DOI Listing

An Oncometabolite Isomer Rapidly Induces a Pathophysiological Protein Modification.

ACS Chem Biol 2020 04 6;15(4):856-861. Epub 2020 Apr 6.

Chemical Biology Laboratory, National Cancer Institute, Frederick Maryland 21702, United States.

Metabolites regulate protein function via covalent and noncovalent interactions. However, manipulating these interactions in living cells remains a major challenge. Here, we report a chemical strategy for inducing cysteine S-succination, a nonenzymatic post-translational modification derived from the oncometabolite fumarate. Read More

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http://dx.doi.org/10.1021/acschembio.0c00044DOI Listing