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    Heterologous Gene Expression of N-terminally truncated variants of LipPks1 Suggests a Functionally Critical Structural Motif in the N-terminus of Modular Polyketide Synthase.
    ACS Chem Biol 2017 Oct 13. Epub 2017 Oct 13.
    Streptomyces genomes have a high G + C content and typically use an ATG or GTG codon to initiate protein synthesis. Although gene-finding tools perform well in low GC genomes, it is known that the accuracy in predicting a translational start site (TSS) is much less for high GC genomes. LipPks1 is a Streptomyces-derived, well-characterized modular polyketide synthase (PKS). Read More

    Discovery of a Distinct Chemical and Mechanistic Class of Allosteric HIV-1 Integrase Inhibitors with Antiretroviral Activity.
    ACS Chem Biol 2017 Oct 12. Epub 2017 Oct 12.
    Allosteric integrase inhibitors (ALLINIs) bind to the lens epithelial-derived growth factor (LEDGF) pocket on HIV-1 integrase (IN) and possess potent antiviral effects. Rather than blocking proviral integration, ALLINIs trigger IN conformational changes that have catastrophic effects on viral maturation, rendering the virions assembled in the presence of ALLINIs non-infectious. A high-throughput screen for compounds that disrupt the IN·LEDGF interaction was executed, and extensive triage led to the identification of a t-butylsulfonamide series, as exemplified by 1. Read More

    Photocontrol of the Hv1 proton channel.
    ACS Chem Biol 2017 Oct 12. Epub 2017 Oct 12.
    The voltage-gated proton channel Hv1 is expressed in various human cell types, including macrophages, epithelial cells, and sperm. Hv1 opening leads to proton efflux that alkalizes the cytosol. Here, we describe light-activated Hv1 inhibitors (photoswitches) that allow controlling its activity with high spatiotemporal precision. Read More

    The promise and challenge of in vivo delivery for genome therapeutics.
    ACS Chem Biol 2017 Oct 11. Epub 2017 Oct 11.
    CRISPR-based genome editing technologies are poised to enable countless new therapies to prevent, treat or cure diseases with a genetic basis. However, the safe and effective delivery of genome editing enzymes represents a substantial challenge that must be tackled to enable the next generation of genetic therapies. In this perspective we summarize recent progress in developing enzymatic tools to combat genetic disease and examine current efforts to deliver these enzymes to the cells in need of correction. Read More

    Intracellular protein delivery system using a target-specific repebody and translocation domain of bacterial exotoxin.
    ACS Chem Biol 2017 Oct 11. Epub 2017 Oct 11.
    With the high efficacy of protein-based therapeutics and a plenty of intracellular drug targets, cytosolic protein delivery in a cell-specific manner has attracted considerable attention in the field of precision medicine. Herein, we present an intracellular protein delivery system based on a target-specific repebody and the translocation domain of Pseudomonas aeruginosa exotoxin A. The delivery platform was constructed by genetically fusing an EGFR-specific repebody as a targeting moiety to the translocation domain, while a protein cargo was fused to the C-terminal end of the delivery platform. Read More

    Genome Editing: Insights from Chemical Biology to Support Safe and Transformative Therapeutic Applications.
    ACS Chem Biol 2017 Oct 9. Epub 2017 Oct 9.
    Programmable nuclease-based genome editing technologies, including the clustered, regularly interspaced, short palindromic repeats (CRISPR)/Cas9 system, are becoming an essential component of many applications ranging from agriculture to medicine. However, fundamental limitations including the potential for off-target effects, limited control of editing activity and subsequent DNA repair outcomes, and insufficient target conversion and delivery performance prevent the widespread, safe, and practical use of genome editors, especially for human disease interventions. This perspective focuses on the potential for biological chemistry to address these limitations such that newly developed genome editing technologies can enable the broadest range of potential future applications. Read More

    Structural Insight into Acyl-ACP Thioesterase toward Substrate Specificity Design.
    ACS Chem Biol 2017 Oct 16. Epub 2017 Oct 16.
    Marine Bioengineering Group, Dalian Institute of Chemical Physics, Chinese Academy of Sciences , Dalian 116023, China.
    Acyl-ACP thioesterase (TE) catalyzes the hydrolysis of thioester bonds during type II fatty acid synthesis and directly determines fatty acid chain length. Most TEs are responsible for recognition of 16:0 and 18:1 substrates, while specific TEs interrupt acyl-ACP elongation at C8-C14. However, the acyl selection mechanism of TE has not been thoroughly elucidated to date. Read More

    Selective Targeting of Vibrios by Fluorescent Siderophore-Based Probes.
    ACS Chem Biol 2017 Oct 16. Epub 2017 Oct 16.
    Department of Chemistry, National Taiwan University , Taipei, 10617, Taiwan (Republic of China).
    Siderophores are small molecules used to specifically transport iron into bacteria via related receptors. By adapting siderophores and hijacking their pathways, we may discover an efficient and selective way to target microbes. Herein, we report the synthesis of a siderophore-fluorophore conjugate VF-FL derived from vibrioferrin (VF). Read More

    Discovery of a selective allosteric inhibitor targeting macrodomain 2 of poly-adenosine-diphosphate-ribose polymerases 14.
    ACS Chem Biol 2017 Oct 9. Epub 2017 Oct 9.
    Macrodomains are conserved protein interaction modules that can be found in all domains of life as well as in certain viruses. Macrodomains mediate recognition of sequence motifs harbouring adenosine diphosphate ribose (ADPR) modifications, thereby regulating a variety of cellular processes. Due to their role in cancer or viral pathogenesis, macrodomains have emerged as potential therapeutic targets, but the unavailability of small molecule inhibitors has hampered target validation studies so far. Read More

    Novel Electrophilic Scaffold for Imaging of Essential Penicillin-Binding Proteins in Streptococcus pneumoniae.
    ACS Chem Biol 2017 Oct 9. Epub 2017 Oct 9.
    Peptidoglycan (PG) is a mesh-like heteropolymer made up of glycan chains crosslinked by short peptides and is the major scaffold of eubacterial cell walls, determining cell shape, size and chaining. This structure, which is required for growth and survival, is located outside of the cytoplasmic membrane of bacterial cells making it highly accessible to antibiotics. Penicillin-binding proteins (PBPs) are essential for construction of PG and perform transglycosylase activities to generate the glycan strands and transpeptidation to crosslink the appended peptides. Read More

    Biosynthesis of (-)-5-hydroxy-equol and 5-hydroxy-dehydroequol from soy isoflavone, genistein using microbial whole cell bioconversion.
    ACS Chem Biol 2017 Oct 6. Epub 2017 Oct 6.
    Equols are isoflavandiols formed by reduction of soy isoflavones such as daidzein and genistein by gut microorganisms. These phytoestrogens are of interest for their various biological effects. We report biosynthesis from genistein to (-)-5-hydroxy-equol in recombinant E. Read More

    Sequence and Solution Effects on the Prevalence of D isomers Produced by Deamidation.
    ACS Chem Biol 2017 Oct 6. Epub 2017 Oct 6.
    Deamidation of asparagine is a spontaneous and irreversible post-translational modification associated with a growing list of human diseases. While pervasive, deamidation is often overlooked because it represents a relatively minor chemical change. Structural and functional characterization of this modification is complicated because deamidation of asparagine yields four isomeric forms of Asp. Read More

    Thioholgamides - thioamide-containing cytotoxic RiPPs natural products.
    ACS Chem Biol 2017 Oct 5. Epub 2017 Oct 5.
    Thioviridamide is a structurally unique ribosomally synthesized and post-translationally modified peptide (RiPP), which contains several thioamide bonds and is active against a number of cancer cell lines. In the search for naturally occurring thioviridamide analogues, we employed genome mining that led to the identification of several related gene clusters. Chemical screening followed by cultivation and isolation yielded thioholgamide A and B, two new additions to the thioviridamide family, with several amino acid substitutions, a different N-capping moiety and with one less thioamide bond. Read More

    Development of 5N-Bicalutamide, A High-affinity Reversible Covalent Antiandrogen.
    ACS Chem Biol 2017 Oct 5. Epub 2017 Oct 5.
    Resistance to clinical antiandrogens has plagued the evolution of effective therapeutics for advanced prostate cancer. As with the first-line therapeutic bicalutamide (Casodex), resistance to newer antiandrogens (enzalutamide, ARN-509) develops quickly in patients, despite the fact that these drugs have ~10-fold better affinity for androgen receptor than bicalutamide. Improving affinity alone is often not sufficient to prevent resistance and alternative strategies are needed to improve antiandrogen efficacy. Read More

    Targeted Disruption of Myc-Max Oncoprotein Complex by a Small Molecule.
    ACS Chem Biol 2017 Oct 11. Epub 2017 Oct 11.
    California Institute for Biomedical Research , La Jolla, California 92037, United States.
    Myc plays important roles in cell cycle progression, cell growth, and stem cell self-renewal. Although dysregulation of Myc expression is a hallmark of human cancers, there is no Myc targeted therapy yet. Here, we report sAJM589, a novel small molecule Myc inhibitor, identified from a PCA-based high-throughput screen. Read More

    A Genomics-Based Approach Identifies a Thioviridamide-Like Compound with Selective Anticancer Activity.
    ACS Chem Biol 2017 Oct 12. Epub 2017 Oct 12.
    Department of Molecular Microbiology, John Innes Centre , Colney Lane, Norwich, NR4 7UH, United Kingdom.
    Thioviridamide is a structurally novel ribosomally synthesized and post-translational modified peptide (RiPP) produced by Streptomyces olivoviridis NA005001. It is characterized by a structure that features a series of thioamide groups and possesses potent antiproliferative activity in cancer cell lines. Its unusual structure allied to its promise as an anticancer compound led us to investigate the diversity of thioviridamide-like pathways across sequenced bacterial genomes. Read More

    Editing the Genome Without Double-Stranded DNA Breaks.
    ACS Chem Biol 2017 Oct 9. Epub 2017 Oct 9.
    Broad Institute of MIT and Harvard , Cambridge, Massachusetts 021413, United States.
    Genome editing methods have commonly relied on the initial introduction of double-stranded DNA breaks (DSBs), resulting in stochastic insertions, deletions, and translocations at the target genomic locus. To achieve gene correction, these methods typically require the introduction of exogenous DNA repair templates and low-efficiency homologous recombination processes. In this review, we describe alternative, mechanistically motivated strategies to perform chemistry on the genome of unmodified cells without introducing DSBs. Read More

    EcoSynther: A Customized Platform To Explore the Biosynthetic Potential in E. coli.
    ACS Chem Biol 2017 Oct 12. Epub 2017 Oct 12.
    Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200333, People's Republic of China.
    Developing computational tools for a chassis-centered biosynthetic pathway design is very important for a productive heterologous biosynthesis system by considering enormous foreign biosynthetic reactions. For many cases, a pathway to produce a target molecule consists of both native and heterologous reactions when utilizing a microbial organism as the host organism. Due to tens of thousands of biosynthetic reactions existing in nature, it is not trivial to identify which could be served as heterologous ones to produce the target molecule in a specific organism. Read More

    Observation by Real-Time NMR and Interpretation of Length- and Location-Dependent Deamination Activity of APOBEC3B.
    ACS Chem Biol 2017 Oct 3. Epub 2017 Oct 3.
    Institute of Advanced Energy and Graduate School of Energy Science, Kyoto University , Gokasho, Uji, 611-0011, Kyoto, Japan.
    Human APOBEC3B (A3B) deaminates a cytosine into a uracil in single-stranded (ss) DNA, resulting in human cancers. A3B's deamination activity is conferred by its C-terminal domain (CTD). However, little is known about the mechanism by which target sequences are searched and deaminated. Read More

    Assaying RNA Localization in Situ with Spatially Restricted Nucleobase Oxidation.
    ACS Chem Biol 2017 Oct 9. Epub 2017 Oct 9.
    Department of Pharmaceutical Sciences and ‡Department of Chemistry, University of California, Irvine , Irvine, California 92697, United States.
    We report herein a novel chemical-genetic method for assaying RNA localization within living cells. RNA localization is critical for normal physiology as well as the onset of cancer and neurodegenerative disorders. Despite its importance, there is a real lack of chemical methods to directly assay RNA localization with high resolution in living cells. Read More

    Identifying Dysregulated Epigenetic Enzyme Activity in Castrate-Resistant Prostate Cancer Development.
    ACS Chem Biol 2017 Oct 11. Epub 2017 Oct 11.
    Department of Biomolecular Chemistry, University of Wisconsin , Madison, Wisconsin 53706, United States.
    There is a tremendous need for novel strategies aimed at directly assessing activities of histone modifiers to probe epigenetic determinants associated with disease progression. Here, we developed a high-throughput peptide microarray assay to identify altered histone lysine (de)acetylation activity in prostate cancer (PCa). This microarray-based activity assay revealed up-regulated histone acetyltransferase (HAT) activity against specific histone H3 sites in a castrate-resistant (CR) PCa cell line compared to its hormone-sensitive (HS) isogenic counterpart. Read More

    A rationally designed agonist defines subfamily IIIA ABA receptors as critical targets for manipulating transpiration.
    ACS Chem Biol 2017 Sep 26. Epub 2017 Sep 26.
    Increasing drought and diminishing freshwater supplies have stimulated interest in developing chemicals that can be used to control transpiration. Receptors for the plant hormone abscisic acid (ABA) have emerged as key targets for this application, because ABA controls the apertures of stomata, which in turn regulate transpiration. Here we describe the rational design of cyanabactin, an ABA receptor agonist that preferentially activates Pyrabactin resistance 1 (PYR1) with low nM potency. Read More

    Oligomerization State of CXCL4 Chemokines Regulates G Protein-Coupled Receptor Activation.
    ACS Chem Biol 2017 Oct 4. Epub 2017 Oct 4.
    INSERM U1029 , 33615 Pessac, France.
    CXCL4 chemokines have antiangiogenic properties, mediated by different mechanisms, including CXCR3 receptor activation. Chemokines have distinct oligomerization states that are correlated with their biological functions. CXCL4 exists as a stable tetramer under physiological conditions. Read More

    Targeting the Hemopexin-like Domain of Latent Matrix Metalloproteinase-9 (proMMP-9) with a Small Molecule Inhibitor Prevents the Formation of Focal Adhesion Junctions.
    ACS Chem Biol 2017 Oct 10. Epub 2017 Oct 10.
    Department of Chemistry, Stony Brook University , Stony Brook, New York, United States.
    A lack of target specificity has greatly hindered the success of inhibitor development against matrix metalloproteinases (MMPs) for the treatment of various cancers. The MMP catalytic domains are highly conserved, whereas the hemopexin-like domains of MMPs are unique to each family member. The hemopexin-like domain of MMP-9 enhances cancer cell migration through self-interaction and heterointeractions with cell surface proteins including CD44 and α4β1 integrin. Read More

    Intertwined Precursor Supply during Biosynthesis of the Catecholate-Hydroxamate Siderophores Qinichelins in Streptomyces sp. MBT76.
    ACS Chem Biol 2017 Oct 2. Epub 2017 Oct 2.
    Molecular Biotechnology, Institute of Biology, Leiden University , Sylviusweg 72, 2333 BE, Leiden, The Netherlands.
    The explosive increase in genome sequencing and the advances in bioinformatic tools have revolutionized the rationale for natural product discovery from actinomycetes. In particular, this has revealed that actinomycete genomes contain numerous orphan gene clusters that have the potential to specify many yet unknown bioactive specialized metabolites, representing a huge unexploited pool of chemical diversity. Here, we describe the discovery of a novel group of catecholate-hydroxamate siderophores termed qinichelins (2-5) from Streptomyces sp. Read More

    A Single-Chain Photoswitchable CRISPR-Cas9 Architecture for Light-Inducible Gene Editing and Transcription.
    ACS Chem Biol 2017 Sep 29. Epub 2017 Sep 29.
    Department of Bioengineering, Stanford University , Stanford, California, United States.
    Optical control of CRISPR-Cas9-derived proteins would be useful for restricting gene editing or transcriptional regulation to desired times and places. Optical control of Cas9 functions has been achieved with photouncageable unnatural amino acids or by using light-induced protein interactions to reconstitute Cas9-mediated functions from two polypeptides. However, these methods have only been applied to one Cas9 species and have not been used for optical control of different perturbations at two genes. Read More

    Whole-Genome Shotgun Sequencing of Two β-Proteobacterial Species in Search of the Bulgecin Biosynthetic Cluster.
    ACS Chem Biol 2017 Sep 26. Epub 2017 Sep 26.
    Department of Chemistry, Johns Hopkins University , Baltimore, Maryland 21218, United States.
    We have produced draft whole-genome sequences for two bacterial strains reported to produce the bulgecins as well as NRPS-derived monobactam β-lactam antibiotics. We propose classification of ATCC 31363 as Paraburkholderia acidophila. We further reaffirm that ATCC 31433 (Burkholderia ubonensis subsp. Read More

    Discovery of Oligonucleotide Signaling Mediated by CRISPR-Associated Polymerases Solves Two Puzzles but Leaves an Enigma.
    ACS Chem Biol 2017 Sep 27. Epub 2017 Sep 27.
    National Center for Biotechnology Information, National Library of Medicine , Bethesda, Maryland 20894, United States.
    The signature component of type III CRISPR-Cas systems is the Cas10 protein that consists of two Palm domains homologous to those of DNA and RNA polymerases and nucleotide cyclases and an HD nuclease domain. However, until very recently, the activity of the Palm domains and their role in CRISPR function have not been experimentally established. Most of the type III CRISPR-Cas systems and some type I systems also encompass proteins containing the CARF (CRISPR-associated Rossmann fold) domain that has been predicted to regulate CRISPR functions via nucleotide binding, but its function in CRISPR-Cas remained obscure. Read More

    Two-Color 810 nm STED Nanoscopy of Living Cells with Endogenous SNAP-Tagged Fusion Proteins.
    ACS Chem Biol 2017 Oct 2. Epub 2017 Oct 2.
    Department of NanoBiophotonics, Max-Planck Institute for Biophysical Chemistry , Am Fassberg 11, 37077 Göttingen, Germany.
    A 810 nm STED nanoscopy setup and an appropriate combination of two fluorescent dyes (Si-rhodamine 680SiR and carbopyronine 610CP) have been developed for near-IR live-cell super-resolution imaging. Vimentin endogenously tagged using the CRISPR/Cas9 approach with the SNAP tag, together with a noncovalent tubulin label, provided reliable and cell-to-cell reproducible dual-color confocal and STED imaging of the cytoskeleton in living cells. Read More

    Simultaneous Production of Anabaenopeptins and Namalides by the Cyanobacterium Nostoc sp. CENA543.
    ACS Chem Biol 2017 Sep 29. Epub 2017 Sep 29.
    Department of Food and Environmental Sciences, University of Helsinki , Viikki Biocenter 1, P.O. Box 56, 00014 Helsinki, Finland.
    Anabaenopeptins are a diverse group of cyclic peptides, which contain an unusual ureido linkage. Namalides are shorter structural homologues of anabaenopeptins, which also contain an ureido linkage. The biosynthetic origins of namalides are unknown despite a strong resemblance to anabaenopeptins. Read More

    Mapping Protein Targets of Bioactive Small Molecules Using Lipid-Based Chemical Proteomics.
    ACS Chem Biol 2017 Sep 20. Epub 2017 Sep 20.
    Department of Molecular Medicine, The Skaggs Institute for Chemical Biology, The Scripps Research Institute , La Jolla, California 92037, United States.
    Lipids play critical roles in cell biology, often through direct interactions with proteins. We recently described the use of photoreactive lipid probes combined with quantitative mass spectrometry to globally map lipid-protein interactions, and the effects of drugs on these interactions, in cells. Here, we investigate the broader potential of lipid-based chemical proteomic probes for determining the cellular targets of biologically active small molecules, including natural product derivatives and repurposed drugs of ill-defined mechanisms. Read More

    Live Cell Imaging of Mitochondrial Autophagy with a Novel Fluorescent Small Molecule.
    ACS Chem Biol 2017 Sep 21. Epub 2017 Sep 21.
    Department of Chemistry, Faculty of Science, Fukuoka University , Jonan-Ku, Fukuoka 814-0180, Japan.
    There has been a growing interest in mitophagy, mitochondria-selective autophagy, which plays an essential role in maintaining intracellular homeostasis. We have developed a small-molecule fluorescent probe, Mtphagy Dye, for visualizing mitophagy, which was readily synthesized from a known perylene derivative, perylene-3,4-dicarboxylic anhydride. Mtphagy Dye has suitable fluorescent properties for detecting mitochondrial acidification during mitophagy in the long-wavelength region that does not damage mitochondria. Read More

    BAF180: Its Roles in DNA Repair and Consequences in Cancer.
    ACS Chem Biol 2017 Sep 28. Epub 2017 Sep 28.
    Department of Chemistry, Michigan Technological University , 1400 Townsend Drive, Houghton, Michigan 49931, United States.
    In 2011, Varela et al. reported that the PBRM1 gene is mutated in approximately 40% of clear cell renal cell carcinoma cases. Since then, the number of studies relating PBRM1 mutations to cancers has substantially increased. Read More

    Mapping the Binding Site for Escitalopram and Paroxetine in the Human Serotonin Transporter Using Genetically Encoded Photo-Cross-Linkers.
    ACS Chem Biol 2017 Sep 26. Epub 2017 Sep 26.
    Center for Biopharmaceuticals, Department of Drug Design and Pharmacology, University of Copenhagen , Jagtvej 162, 2100 Copenhagen Ø, Denmark.
    In spite of the important role of the human serotonin transporter (hSERT) in depression treatment, the molecular details of how antidepressant drugs bind are still not completely understood, in particular those related to potential high- and low-affinity binding sites in hSERT. Here, we utilize amber codon suppression in hSERT to encode the photo-cross-linking unnatural amino acid p-azido-l-phenylalanine into the suggested high- and low-affinity binding sites. We then employ UV-induced cross-linking with azF to map the binding site of escitalopram and paroxetine, two prototypical selective serotonin reuptake inhibitors (SSRIs). Read More

    Rheostatic Control of Cas9-Mediated DNA Double Strand Break (DSB) Generation and Genome Editing.
    ACS Chem Biol 2017 Sep 15. Epub 2017 Sep 15.
    Department of Chemistry, University of Washington , Seattle, Washington 98195, United States.
    We recently reported two novel tools for precisely controlling and quantifying Cas9 activity: a chemically inducible Cas9 variant (ciCas9) that can be rapidly activated by small molecules and a ddPCR assay for time-resolved measurement of DNA double strand breaks (DSB-ddPCR). Here, we further demonstrate the potential of ciCas9 to function as a tunable rheostat for Cas9 function. We show that a new highly potent and selective small molecule activator paired with a more tightly regulated ciCas9 variant expands the range of accessible Cas9 activity levels. Read More

    Backbone Circularization Coupled with Optimization of Connecting Segment in Effectively Improving the Stability of Granulocyte-Colony Stimulating Factor.
    ACS Chem Biol 2017 Sep 27. Epub 2017 Sep 27.
    Biomedical Research Institute, The National Institute of Advanced Industrial Science and Technology , Central 6, 1-1-1 Higashi, Tsukuba, Ibaraki 305-8566, Japan.
    Backbone circularization of protein is a powerful method to improve its structural stability. In this paper, we presumed that a tight connection leads to much higher stability. Therefore, we designed circularized variants of a granulocyte-colony stimulating factor (G-CSF) with a structurally optimized terminal connection. Read More

    Platinum Binds Proteins in the Endoplasmic Reticulum of S. cerevisiae and Induces Endoplasmic Reticulum Stress.
    ACS Chem Biol 2017 Sep 28. Epub 2017 Sep 28.
    Department of Chemistry and Institute of Molecular Biology, University of Oregon , Eugene, Oregon 97403, United States.
    Pt(II)-based anticancer drugs are widely used in the treatment of a variety of cancers, but their clinical efficacy is hindered by undesirable side effects and resistance. While much research has focused on Pt(II) drug interactions with DNA, there is increasing interest in proteins as alternative targets and contributors to cytotoxic and resistance mechanisms. Here, we describe a chemical proteomic method for isolation and identification of cellular protein targets of platinum compounds using Pt(II) reagents that have been modified for participation in the 1,3 dipolar cycloaddition "click" reaction. Read More

    Chemoproteomics-Enabled Covalent Ligand Screening Reveals a Thioredoxin-Caspase 3 Interaction Disruptor That Impairs Breast Cancer Pathogenicity.
    ACS Chem Biol 2017 Sep 13. Epub 2017 Sep 13.
    Departments of Chemistry, Molecular and Cell Biology, and ‡Nutritional Sciences and Toxicology, University of California, Berkeley , Berkeley, California 94720, United States.
    Covalent ligand discovery is a promising strategy to develop small-molecule effectors against therapeutic targets. Recent studies have shown that dichlorotriazines are promising reactive scaffolds that preferentially react with lysines. Here, we have synthesized a series of dichlorotriazine-based covalent ligands and have screened this library to reveal small molecules that impair triple-negative breast cancer cell survival. Read More

    CRISPR-Mediated Tagging of Endogenous Proteins with a Luminescent Peptide.
    ACS Chem Biol 2017 Sep 21. Epub 2017 Sep 21.
    Promega Corporation , Madison, Wisconsin 53711, United States.
    Intracellular signaling pathways are mediated by changes in protein abundance and post-translational modifications. A common approach for investigating signaling mechanisms and the effects induced by synthetic compounds is through overexpression of recombinant reporter genes. Genome editing with CRISPR/Cas9 offers a means to better preserve native biology by appending reporters directly onto the endogenous genes. Read More

    Inhibitors of the Diadenosine Tetraphosphate Phosphorylase Rv2613c of Mycobacterium tuberculosis.
    ACS Chem Biol 2017 Sep 26. Epub 2017 Sep 26.
    Department of Chemistry, Konstanz Research School Chemical Biology, University of Konstanz , Universitätsstrasse 10, D-78464 Konstanz, Germany.
    The intracellular concentration of diadenosine tetraphospate (Ap4A) increases upon exposure to stress conditions. Despite being discovered over 50 years ago, the cellular functions of Ap4A are still enigmatic. If and how the varied Ap4A is a signal and involved in the signaling pathways leading to an appropriate cellular response remain to be discovered. Read More

    Two Cooperative Glycosyltransferases Are Responsible for the Sugar Diversity of Saquayamycins Isolated from Streptomyces sp. KY 40-1.
    ACS Chem Biol 2017 Sep 13. Epub 2017 Sep 13.
    Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky , Lexington, Kentucky 40536, United States.
    Glycosyltransferases are key enzymes involved in the biosynthesis of valuable natural products providing an excellent drug-tailoring tool. Herein, we report the identification of two cooperative glycosyltransferases from the sqn gene cluster directing the biosynthesis of saquayamycins in Streptomyces sp. KY40-1: SqnG1 and SqnG2. Read More

    An Anion-π Interaction Strongly Stabilizes the β-Sheet Protein WW.
    ACS Chem Biol 2017 Sep 14. Epub 2017 Sep 14.
    Department of Chemistry and Biochemistry, Brigham Young University , Provo, Utah 84602, United States.
    Anions have long been known to engage in stabilizing interactions with electron-deficient arenes. However, the precise nature and energetic contribution of anion-π interactions to protein stability remains a subject of debate. Here, we show that placing a negatively charged Asp in close proximity to electron-rich Phe in a reverse turn within the WW domain results in a favorable interaction that increases WW conformational stability by -1. Read More

    Exploiting Overlapping Advantages of In Vitro and In Cellulo Selection Systems to Isolate a Novel High-Affinity cJun Antagonist.
    ACS Chem Biol 2017 Sep 7. Epub 2017 Sep 7.
    Dept of Biology and Biochemistry, University of Bath , Claverton Down, Bath BA2 7AY, United Kingdom.
    We have combined two peptide library-screening systems, exploiting the benefits offered by both to select novel antagonistic agents of cJun. CIS display is an in vitro cell-free system that allows very large libraries (≤10(14)) to be interrogated. However, affinity-based screening conditions can poorly reflect those relevant to therapeutic application, particularly for difficult intracellular targets, and can lead to false positives. Read More

    Structural Basis of the Selectivity of GenN, an Aminoglycoside N-Methyltransferase Involved in Gentamicin Biosynthesis.
    ACS Chem Biol 2017 Oct 9. Epub 2017 Oct 9.
    Department of Microbiology, Institute of Biomedical Science, University of São Paulo , São Paulo, Brazil.
    Gentamicins are heavily methylated, clinically valuable pseudotrisaccharide antibiotics produced by Micromonospora echinospora. GenN has been characterized as an S-adenosyl-l-methionine-dependent methyltransferase with low sequence similarity to other enzymes. It is responsible for the 3″-N-methylation of 3″-dehydro-3″-amino-gentamicin A2, an essential modification of ring III in the biosynthetic pathway to the gentamicin C complex. Read More

    Differential Kinobeads Profiling for Target Identification of Irreversible Kinase Inhibitors.
    ACS Chem Biol 2017 Sep 12. Epub 2017 Sep 12.
    Cellzome GmbH, GlaxoSmithKline , Meyerhofstrasse 1, D-69117 Heidelberg, Germany.
    Chemoproteomics profiling of kinase inhibitors with kinobeads enables the assessment of inhibitor potency and selectivity for endogenously expressed protein kinases in cell lines and tissues. Using a small panel of targeted covalent inhibitors, we demonstrate the importance of measuring covalent target binding in live cells. We present a differential kinobeads profiling strategy for covalent kinase inhibitors where a compound is added either to live cells or to a cell extract that enables the comprehensive assessment of inhibitor selectivity for covalent and noncovalent targets. Read More

    Transition State Analysis of Adenosine Triphosphate Phosphoribosyltransferase.
    ACS Chem Biol 2017 Sep 19. Epub 2017 Sep 19.
    Maurice Wilkins Centre, Biomolecular Interaction Centre and Department of Chemistry, University of Canterbury , P.O. Box 4800, Christchurch 8140, New Zealand.
    Adenosine triphosphate phosphoribosyltransferase (ATP-PRT) catalyzes the first step in histidine biosynthesis, a pathway essential to microorganisms and a validated target for antimicrobial drug design. The ATP-PRT enzyme catalyzes the reversible substitution reaction between phosphoribosyl pyrophosphate and ATP. The enzyme exists in two structurally distinct forms, a short- and a long-form enzyme. Read More

    BTN3A1 Discriminates γδ T Cell Phosphoantigens from Nonantigenic Small Molecules via a Conformational Sensor in Its B30.2 Domain.
    ACS Chem Biol 2017 Sep 14. Epub 2017 Sep 14.
    Institute of Immunology and Immunotherapy, University of Birmingham , Edgbaston, Birmingham, United Kingdom , B15 2TT.
    Human Vγ9/Vδ2 T-cells detect tumor cells and microbial infections by recognizing small phosphorylated prenyl metabolites termed phosphoantigens (P-Ag). The type-1 transmembrane protein Butyrophilin 3A1 (BTN3A1) is critical to the P-Ag-mediated activation of Vγ9/Vδ2 T-cells; however, the molecular mechanisms involved in BTN3A1-mediated metabolite sensing are unclear, including how P-Ag's are discriminated from nonantigenic small molecules. Here, we utilized NMR and X-ray crystallography to probe P-Ag sensing by BTN3A1. Read More

    Functional Analysis of Cytochrome P450s Involved in Streptovaricin Biosynthesis and Generation of Anti-MRSA Analogues.
    ACS Chem Biol 2017 Sep 7. Epub 2017 Sep 7.
    Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (Wuhan University), Ministry of Education, and Wuhan University School of Pharmaceutical Sciences , Wuhan 430071, People's Republic of China.
    The streptovaricins, chemically related to the rifamycins, are highly effective antibacterial agents, particularly against mycobacteria. Herein, a bioassay-guided investigation of Streptomyces spectabilis CCTCC M2017417 has led to the characterization of streptovaricins as potent compounds against methicillin-resistant Staphylococcus aureus (MRSA). We identified the streptovaricin biosynthetic gene cluster from S. Read More

    BNA(NC) Gapmers Revert Splicing and Reduce RNA Foci with Low Toxicity in Myotonic Dystrophy Cells.
    ACS Chem Biol 2017 Sep 5. Epub 2017 Sep 5.
    Bio-Synthesis, Inc. , 612 East Main Street, Lewisville, Texas 75057, United States.
    Myotonic dystrophy type 1 (DM1) is a multisystemic disease caused by an expanded CTG repeat in the 3' UTR of the dystrophia myotonica protein kinase (DMPK) gene. Short, DNA-based antisense oligonucleotides termed gapmers are a promising strategy to degrade toxic CUG expanded repeat (CUGexp) RNA. Nucleoside analogs are incorporated to increase gapmer affinity and stability; however, some analogs also exhibit toxicity. Read More

    Ionic Strength Sensing in Living Cells.
    ACS Chem Biol 2017 Sep 6. Epub 2017 Sep 6.
    Department of Biochemistry, Groningen Biomolecular Sciences and Biotechnology Institute & Zernike Institute for Advanced Materials, University of Groningen , Nijenborgh 4, 9747 AG Groningen, The Netherlands.
    Knowledge of the ionic strength in cells is required to understand the in vivo biochemistry of the charged biomacromolecules. Here, we present the first sensors to determine the ionic strength in living cells, by designing protein probes based on Förster resonance energy transfer (FRET). These probes allow observation of spatiotemporal changes in the ionic strength on the single-cell level. Read More

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