3,170 results match your criteria ACS chemical biology[Journal]


Crystal Structure of GenD2, an NAD-Dependent Oxidoreductase Involved in the Biosynthesis of Gentamicin.

ACS Chem Biol 2019 Apr 17. Epub 2019 Apr 17.

Gentamicins are clinically relevant aminoglycoside antibiotics produced by several Micromonospora species. Gentamicins are highly methylated and functionalized molecules and their biosynthesis include glycosyltransferases, dehydratase/oxidoreductases, aminotransferases, and methyltransferases. The biosynthesis of gentamicin A from gentamicin A2 involves three enzymatic steps that modify the hydroxyl group at position 3'' of the unusual garosamine sugar to provide its substitution for an amino group, followed by an N-methylation. Read More

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http://pubs.acs.org/doi/10.1021/acschembio.9b00115
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http://dx.doi.org/10.1021/acschembio.9b00115DOI Listing
April 2019
1 Read

Introducing Our Authors.

Authors:
Brian Wyler

ACS Chem Biol 2018 Oct;13(10):2822-2823

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http://dx.doi.org/10.1021/acschembio.8b00893DOI Listing
October 2018

Evolutionary Trajectories for the Functional Diversification of Anthracycline Methyltransferases.

ACS Chem Biol 2019 Apr 17. Epub 2019 Apr 17.

Microbial natural products are an important source of chemical entities for drug discovery. Recent advances in understanding the biosynthesis of secondary metabolites has revealed how this rich chemical diversity is generated through functional differentiation of biosynthetic enzymes. For instance, investigations into anthracycline anti-cancer agents have uncovered distinct S-adenosyl methionine (SAM) - dependent proteins: DnrK is a 4-O-methyltransferase involved in daunorubicin biosynthesis, whereas RdmB (52% sequence identity) from the rhodomycin pathway catalyzes 10-hydroxylation. Read More

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http://pubs.acs.org/doi/10.1021/acschembio.9b00238
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http://dx.doi.org/10.1021/acschembio.9b00238DOI Listing
April 2019
1 Read

Responsible Peer Review.

Authors:
Katrin Karbstein

ACS Chem Biol 2018 Dec;13(12):3217-3218

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http://dx.doi.org/10.1021/acschembio.8b01035DOI Listing
December 2018

In This Issue, Volume 13, Issue 12.

Authors:
Alyson Weidmann

ACS Chem Biol 2018 Dec;13(12):3220

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http://dx.doi.org/10.1021/acschembio.8b01061DOI Listing
December 2018

In This Issue, Volume 13, Issue 4.

ACS Chem Biol 2018 Apr;13(4):841

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http://dx.doi.org/10.1021/acschembio.8b00310DOI Listing

Antibiotic discovery with synthetic fermentation: library assembly, phenotypic screening, and mechanism of action of beta-peptides targeting penicillin-binding proteins.

ACS Chem Biol 2019 Apr 16. Epub 2019 Apr 16.

In analogy to biosynthetic pathways leading to bioactive natural products, synthetic fermentation generates mixtures of molecules from simple building blocks under aqueous, biocompatible conditions, allowing for the resulting cultures to be directly screened for biological activity. In this work, a novel beta-peptide antibiotic was successfully identified using the synthetic fermentation platform. Phenotypic screening was carried out in an initially random fashion, allowing for simple identification of active cultures. Read More

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http://pubs.acs.org/doi/10.1021/acschembio.9b00227
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http://dx.doi.org/10.1021/acschembio.9b00227DOI Listing
April 2019
4 Reads

Characterization of lipid binding properties of Plasmodium falciparum acyl-CoA binding proteins and their competitive inhibition by mefloquine.

ACS Chem Biol 2019 Apr 15. Epub 2019 Apr 15.

Malaria remains a worldwide concern in terms of morbidity and mortality. Limited understanding of Plasmodium proteome makes it challenging to control malaria. Understanding of the expression and functions of different Plasmodium proteins will help in knowing this organism's virulence properties, other than facilitating the drug development process. Read More

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http://pubs.acs.org/doi/10.1021/acschembio.9b00003
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http://dx.doi.org/10.1021/acschembio.9b00003DOI Listing
April 2019
1 Read

Biocatalytic Detoxification of Paralytic Shellfish Toxins.

ACS Chem Biol 2019 Apr 15. Epub 2019 Apr 15.

United States Food and Drug Administration , College Park , Maryland 20740 , United States.

Small molecules that bind to voltage-gated sodium channels (VGSCs) are promising leads in the treatment of numerous neurodegenerative diseases and pain. Nature is a highly skilled medicinal chemist in this regard, designing potent VGSC ligands capable of binding to and blocking the channel, thereby offering compounds of potential therapeutic interest. Paralytic shellfish toxins (PSTs), produced by cyanobacteria and marine dinoflagellates, are examples of these naturally occurring small molecule VGSC blockers that can potentially be leveraged to solve human health concerns. Read More

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http://pubs.acs.org/doi/10.1021/acschembio.9b00123
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April 2019
1 Read

Rapid and reversible knockdown of endogenously tagged endosomal proteins via an optimized HaloPROTAC degrader.

ACS Chem Biol 2019 Apr 12. Epub 2019 Apr 12.

Inducing post-translational protein knockdown is an important approach to probe biology and validate drug targets. An efficient strategy to achieve this involves expression of a protein of interest fused to an exogenous tag, allowing tag-directed chemical degraders to mediate protein ubiquitylation and proteasomal degradation. Here, we combine improved HaloPROTAC degrader probes with CRISPR/Cas9 genome editing technology to trigger rapid degradation of endogenous target proteins. Read More

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http://dx.doi.org/10.1021/acschembio.8b01016DOI Listing

Structure of Sesquisabinene Synthase 1, a Terpenoid Cyclase that Generates a Strained [3.1.0] Bridged-Bicyclic Product.

ACS Chem Biol 2019 Apr 12. Epub 2019 Apr 12.

The natural product sesquisabinene is a key component of the fragrant essential oil of the sandalwood tree, currently valued at $5,000/L. Sesquisabinene contains a highly strained [3.1. Read More

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http://pubs.acs.org/doi/10.1021/acschembio.9b00218
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http://dx.doi.org/10.1021/acschembio.9b00218DOI Listing
April 2019
1 Read

Amino acid residues recognizing isomeric glutamate substrates in UDP- N-acetylmuramic acid-L-alanine-glutamate synthetases.

ACS Chem Biol 2019 Apr 12. Epub 2019 Apr 12.

We recently revealed that a previously unknown pathway for peptidoglycan biosynthesis operates in some microorganisms, including Xanthomonas oryzae. It involves two enzymes, MurD2 and MurL, which catalyze the ligation of L-glutamate (L-Glu) to UDP- N-acetylmuramic acid-L-alanine and the epimerization of the terminal L-Glu of the product, respectively. MurD2 of X. Read More

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http://dx.doi.org/10.1021/acschembio.9b00159DOI Listing

An ancient peptide family buried within vicilin precursors.

ACS Chem Biol 2019 Apr 11. Epub 2019 Apr 11.

New proteins can evolve by duplication and divergence or de novo, from previously non-coding DNA. A recently observed mechanism is for peptides to evolve within a 'host' protein and emerge by proteolytic processing. The first examples of such interstitial peptides were ones hosted by precursors for seed storage albumin. Read More

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http://dx.doi.org/10.1021/acschembio.9b00167DOI Listing

The Transferrin Cycle and Clinical Roles of Citrate and Ascorbate in Improved Iron Metabolism.

ACS Chem Biol 2019 Apr 11. Epub 2019 Apr 11.

Fe(III) delivery from blood plasma to cells via the transferrin (Tf) cycle is studied intensively due to its crucial role in Fe homeostasis. Tf-cycle disruptions are linked to anemia, infections, immunodeficiency and neurodegeneration. Bio-layer interferometry (BLI) enabled direct kinetic and thermodynamic measurements for all Tf-cycle steps in a single in-vitro experiment using Tf within blood serum or released into the medium by cultured liver cells. Read More

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http://dx.doi.org/10.1021/acschembio.8b01100DOI Listing
April 2019
1 Read

Novel antimycobacterial compounds suppress NAD biogenesis by targeting a unique pocket of NaMN adenylyltransferase.

ACS Chem Biol 2019 Apr 10. Epub 2019 Apr 10.

Conventional treatments to combat Tuberculosis (TB) epidemic are falling short, thus encouraging the search for novel antitubercular drugs acting on unexplored molecular targets. Several whole cell phenotypic screenings have delivered bioactive compounds with potent antitubercular activity. However, their cellular target and mechanism of action remain largely unknown. Read More

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http://dx.doi.org/10.1021/acschembio.9b00124DOI Listing
April 2019
1 Read

ATP-independent bioluminescent reporter variants to improve in vivo imaging.

ACS Chem Biol 2019 Apr 10. Epub 2019 Apr 10.

Coelenterazine (CTZ)-utilizing marine luciferases and their derivatives have attracted significant attention because of their ATP-independency, fast enzymatic turnover, and high bioluminescence brightness. However, marine luciferases typically emit blue photons and their substrates, including CTZ and the recently developed diphenylterazine (DTZ), have poor water solubility, hindering their in vivo applications. Herein, we report a family of pyridyl CTZ and DTZ analogs that exhibit spectrally shifted emission and improved water solubility. Read More

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http://pubs.acs.org/doi/10.1021/acschembio.9b00150
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April 2019
2 Reads

Computer-Aided Discovery of Massonianoside B as a Novel Selective DOT1L Inhibitor.

ACS Chem Biol 2019 Apr 16. Epub 2019 Apr 16.

School of Pharmacy , Sungkyunkwan University , Suwon , Gyeonggi-do 16419 , South Korea.

Protein methyltransferases (PMTs) are involved in numerous biological processes and have been studied as a promising target class in the field of oncology and other diseases. Disruptor of telomeric silencing 1-like (DOT1L), a histone H3 lysine 79 (H3K79) methyltransferase, plays an important role in the progressions of mixed-lineage leukemia (MLL)-rearranged leukemias and has been validated as a potential therapeutic target. Here we report the discovery and characterization of a novel DOT1L inhibitor, massonianoside B (MA), by pharmacophore-based in silico screening and biological studies. Read More

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http://pubs.acs.org/doi/10.1021/acschembio.8b00933
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April 2019
1 Read

Unique Polypharmacology Nuclear Receptor Modulator Blocks Inflammatory Signaling Pathways.

ACS Chem Biol 2019 Apr 15. Epub 2019 Apr 15.

Department of Molecular Medicine , The Scripps Research Institute , Jupiter , Florida 33458 , United States.

Obesity and rheumatic disease are mechanistically linked via chronic inflammation. The orphan receptor TREM-1 (triggering receptor expressed on myeloid cells-1) is a potent amplifier of proinflammatory and noninfectious immune responses. Here, we show that the pan modulator SR1903 effectively blocks TREM-1 activation. Read More

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http://pubs.acs.org/doi/10.1021/acschembio.9b00236
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http://dx.doi.org/10.1021/acschembio.9b00236DOI Listing
April 2019
3 Reads
5.331 Impact Factor

Small Molecule and Pooled CRISPR Screens Investigating IL17 Signaling Identify BRD2 as a Novel Contributor to Keratinocyte Inflammatory Responses.

ACS Chem Biol 2019 Apr 15. Epub 2019 Apr 15.

Discovery Dermatology & Fibrosis , AbbVie Bioresearch Center , Worcester , Massachusetts 01605 , United States.

Interleukin-17A (IL17A) plays a critical role in the development of numerous autoimmune diseases, including psoriasis. The clinical success of IL17A neutralizing biologics in psoriasis has underlined its importance as a drug discovery target. While many studies have focused on the differentiation and trafficking of IL17A producing T-helper 17 cells, less is known about IL17A-initiated signaling events in stromal and parenchymal cells leading to psoriatic phenotypes. Read More

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http://pubs.acs.org/doi/10.1021/acschembio.8b00260
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http://dx.doi.org/10.1021/acschembio.8b00260DOI Listing
April 2019
3 Reads

Engineered Aminoacyl-tRNA Synthetases with Improved Selectivity toward Noncanonical Amino Acids.

ACS Chem Biol 2019 Apr 9. Epub 2019 Apr 9.

Department of Molecular Biophysics and Biochemistry , Yale University , New Haven , Connecticut 06520 , United States.

A wide range of noncanonical amino acids (ncAAs) can be incorporated into proteins in living cells by using engineered aminoacyl-tRNA synthetase/tRNA pairs. However, most engineered tRNA synthetases are polyspecific; that is, they can recognize multiple rather than one ncAA. Polyspecificity of engineered tRNA synthetases imposes a limit to the use of genetic code expansion because it prevents specific incorporation of a desired ncAA when multiple ncAAs are present in the growth media. Read More

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http://dx.doi.org/10.1021/acschembio.9b00088DOI Listing
April 2019
5.331 Impact Factor

A trans-Acting Cyclase Offloading Strategy for Nonribosomal Peptide Synthetases.

ACS Chem Biol 2019 Apr 8. Epub 2019 Apr 8.

Department of Chemistry , University of Warwick , Coventry CV4 7AL , United Kingdom.

The terminal step in the biosynthesis of nonribosomal peptides is the hydrolytic release and, frequently, macrocyclization of an aminoacyl-S-thioester by an embedded thioesterase. The surugamide biosynthetic pathway is composed of two nonribosomal peptide synthetase (NRPS) assembly lines in which one produces surugamide A, which is a cyclic octapeptide, and the other produces surugamide F, a linear decapeptide. The terminal module of each system lacks an embedded thioesterase, which led us to question how the peptides are released from the assembly line (and cyclized in the case of surugamide A). Read More

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http://dx.doi.org/10.1021/acschembio.9b00095DOI Listing
April 2019
2 Reads

Bioinformatic and Functional Evaluation of Actinobacterial Piperazate Metabolism.

ACS Chem Biol 2019 Apr 9. Epub 2019 Apr 9.

Department of Biology , Washington University in St. Louis , 1 Brookings Drive , St. Louis , Missouri 63130 , United States.

Piperazate (Piz) is a nonproteinogenic amino acid noted for its unusual N-N bond motif. Piz is a proline mimic that imparts conformational rigidity to peptides. Consequently, piperazyl molecules are often bioactive and desirable for therapeutic exploration. Read More

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http://dx.doi.org/10.1021/acschembio.8b01086DOI Listing
April 2019
1 Read

A Unified Framework for the Incorporation of Bioorthogonal Compound Exposure Probes within Biological Compartments.

ACS Chem Biol 2019 Apr 5. Epub 2019 Apr 5.

Novartis Institutes for BioMedical Research , Emerville , California 94608 , United States.

Compartmentalization is a crucial facet of many biological systems, and key aspects of cellular processes rely on spatial segregation within the cell. While many drug targets reside in specific intracellular compartments, the tools available for assessing compound exposure are generally limited to whole-cell measurements. To address this gap, we recently developed a bioorthogonal chemistry-based method to assess compartment-specific compound exposure and demonstrated its use in Gram-negative bacteria. Read More

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http://dx.doi.org/10.1021/acschembio.9b00008DOI Listing
April 2019
1 Read

Chemoproteomic Selectivity Profiling of PIKK and PI3K Kinase Inhibitors.

ACS Chem Biol 2019 Apr 3. Epub 2019 Apr 3.

German Cancer Consortium (DKTK), Munich , Germany.

Chemical proteomic approaches utilizing immobilized, broad-selective kinase inhibitors (Kinobeads) have proven valuable for the elucidation of a compound's target profile under close-to-physiological conditions and often revealed potentially synergistic or toxic off-targets. Current Kinobeads enrich more than 300 native protein kinases from cell line or tissue lysates but do not systematically cover phosphatidylinositol 3-kinases (PI3Ks) and phosphatidylinositol 3-kinase-related kinases (PIKKs). Some PIKKs and PI3Ks show aberrant activation in many human diseases and are indeed validated drug targets. Read More

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http://dx.doi.org/10.1021/acschembio.8b01020DOI Listing
April 2019
2 Reads

MAGI: A Method for Metabolite Annotation and Gene Integration.

ACS Chem Biol 2019 Apr 4. Epub 2019 Apr 4.

Environmental Genomics and Systems Biology Division , Lawrence Berkeley National Laboratory , Berkeley , California 94720 , United States.

Metabolomics is a widely used technology for obtaining direct measures of metabolic activities from diverse biological systems. However, ambiguous metabolite identifications are a common challenge and biochemical interpretation is often limited by incomplete and inaccurate genome-based predictions of enzyme activities (that is, gene annotations). Metabolite Annotation and Gene Integration (MAGI) generates a metabolite-gene association score using a biochemical reaction network. Read More

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http://dx.doi.org/10.1021/acschembio.8b01107DOI Listing

Hyperpolarized [6-C,N]-Arginine as a Probe for in Vivo Arginase Activity.

ACS Chem Biol 2019 Mar 27. Epub 2019 Mar 27.

Department of Biochemistry and Structural Biology , Weill Cornell Graduate School , New York , New York 10065 , United States.

Alterations in arginase enzyme expression are linked with various diseases and have been shown to support disease progression, thus motivating the development of an imaging probe for this enzymatic target. C-enriched arginine can be used as a hyperpolarized (HP) magnetic resonance (MR) probe for arginase flux since the arginine carbon-6 resonance (157 ppm) is converted to urea (163 ppm) following arginase-catalyzed hydrolysis. However, scalar relaxation from adjacent N-nuclei shortens cabon-6 T and T times, yielding poor spectral properties. Read More

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http://pubs.acs.org/doi/10.1021/acschembio.8b01044
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http://dx.doi.org/10.1021/acschembio.8b01044DOI Listing
March 2019
6 Reads

Norbornene Probes for the Detection of Cysteine Sulfenic Acid in Cells.

ACS Chem Biol 2019 Mar 26. Epub 2019 Mar 26.

Flinders University , College of Science and Engineering , Sturt Road , Bedford Park , South Australia 5042 , Australia.

Norbornene derivatives were validated as probes for cysteine sulfenic acid on proteins and in live cells. Trapping sulfenic acids with norbornene probes is highly selective and revealed a different reactivity profile than the traditional dimedone reagent. The norbornene probe also revealed a superior chemoselectivity when compared to a commonly used dimedone probe. Read More

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http://dx.doi.org/10.1021/acschembio.8b01104DOI Listing

In This Issue, Volume 14, Issue 1.

ACS Chem Biol 2019 Jan;14(1)

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http://dx.doi.org/10.1021/acschembio.9b00017DOI Listing
January 2019

Engineering Na1.7 Inhibitory JzTx-V Peptides with a Potency and Basicity Profile Suitable for Antibody Conjugation To Enhance Pharmacokinetics.

ACS Chem Biol 2019 Mar 27. Epub 2019 Mar 27.

Drug discovery research on new pain targets with human genetic validation, including the voltage-gated sodium channel Na1.7, is being pursued to address the unmet medical need with respect to chronic pain and the rising opioid epidemic. As part of early research efforts on this front, we have previously developed Na1. Read More

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http://dx.doi.org/10.1021/acschembio.9b00183DOI Listing

In This Issue, Volume 14, Issue 3.

Authors:
Alyson Weidmann

ACS Chem Biol 2019 Mar;14(3):315

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http://dx.doi.org/10.1021/acschembio.9b00179DOI Listing

Meeting Proceedings from ICBS 2018- Toward Translational Impact.

ACS Chem Biol 2019 Mar 12. Epub 2019 Mar 12.

The Department of Data Science , The Institute of Cancer Research , London , SM2 5NG , United Kingdom.

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http://pubs.acs.org/doi/10.1021/acschembio.9b00169
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http://dx.doi.org/10.1021/acschembio.9b00169DOI Listing
March 2019
1 Read

A Chemical Inhibitor of Cell Growth Reduces Cell Size in Bacillus subtilis.

ACS Chem Biol 2019 Mar 18. Epub 2019 Mar 18.

Department of Biochemistry , University of Toronto , Toronto , Ontario M5S 1A8 , Canada.

Bacteria exhibit complex responses to biologically active small molecules. These responses include reductions in transcriptional and translational efficiency, alterations in metabolic flux, and in some cases, dramatic changes in growth and morphology. Here, we describe Min-1, a novel small molecule that inhibits growth of Gram-positive bacteria by targeting the cell envelope. Read More

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http://pubs.acs.org/doi/10.1021/acschembio.8b01066
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http://dx.doi.org/10.1021/acschembio.8b01066DOI Listing
March 2019
2 Reads

Directed Evolution of Split APEX2 Peroxidase.

ACS Chem Biol 2019 Mar 8. Epub 2019 Mar 8.

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

APEX is an engineered peroxidase that catalyzes the oxidation of a wide range of substrates, facilitating its use in a variety of applications from subcellular staining for electron microscopy to proximity biotinylation for spatial proteomics and transcriptomics. To further advance the capabilities of APEX, we used directed evolution to engineer a split APEX tool (sAPEX). A total of 20 rounds of fluorescence activated cell sorting (FACS)-based selections from yeast-displayed fragment libraries, using 3 different surface display configurations, produced a 200-amino-acid N-terminal fragment (with 9 mutations relative to APEX2) called "AP" and a 50-amino-acid C-terminal fragment called "EX". Read More

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http://pubs.acs.org/doi/10.1021/acschembio.8b00919
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http://dx.doi.org/10.1021/acschembio.8b00919DOI Listing
March 2019
4 Reads

Reverse Chemical Proteomics Identifies an Unanticipated Human Target of the Antimalarial Artesunate.

ACS Chem Biol 2019 Mar 19. Epub 2019 Mar 19.

Department of Molecular Sciences , Macquarie University , Sydney , NSW 2109 , Australia.

Artemisinins are the most potent and safe antimalarials available. Despite their clinical potential, no human target for the artemisinins is known. The unbiased interrogation of several human cDNA libraries, displayed on bacteriophage T7, revealed a single human target of artesunate; the intrinsically disordered Bcl-2 antagonist of cell death promoter (BAD). Read More

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http://dx.doi.org/10.1021/acschembio.8b01004DOI Listing
March 2019
5 Reads

Colloidal Drug Aggregate Stability in High Serum Conditions and Pharmacokinetic Consequence.

ACS Chem Biol 2019 Mar 12. Epub 2019 Mar 12.

Department of Chemical Engineering and Applied Chemistry , University of Toronto , 200 College Street , Toronto , Ontario M5S 3E5 , Canada.

Colloidal drug aggregates have been a nuisance in drug screening, yet, because they inherently comprise drug-rich particles, they may be useful in vivo if issues of stability can be addressed. As the first step toward answering this question, we optimized colloidal drug aggregate formulations using a fluorescence-based assay to study fulvestrant colloidal formation and stability in high (90%) serum conditions in vitro. We show, for the first time, that the critical aggregation concentration of fulvestrant depends on media composition and increases with serum concentration. Read More

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http://dx.doi.org/10.1021/acschembio.9b00032DOI Listing

The STAT5b Linker Domain Mediates the Selectivity of Catechol Bisphosphates for STAT5b over STAT5a.

ACS Chem Biol 2019 Mar 18. Epub 2019 Mar 18.

Institute of Organic Chemistry , Leipzig University , Johannisallee 29 , 04103 Leipzig , Germany.

STAT family proteins are important mediators of cell signaling and represent therapeutic targets for the treatment of human diseases. Most STAT inhibitors target the protein-protein interaction domain, the SH2 domain, but specificity for a single STAT protein is often limited. Recently, we developed catechol bisphosphates as the first inhibitors of STAT5b demonstrated to exhibit a high degree of selectivity over the close homologue STAT5a. Read More

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http://dx.doi.org/10.1021/acschembio.9b00137DOI Listing
March 2019
2 Reads

Exploiting CD22 To Selectively Tolerize Autoantibody Producing B-Cells in Rheumatoid Arthritis.

ACS Chem Biol 2019 Mar 20. Epub 2019 Mar 20.

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

Rheumatoid arthritis (RA) is an autoimmune disease that primarily affects the synovial joints and can lead to bone erosion and cartilage damage. One hallmark of RA is anticitrullinated protein autoantibodies (ACPA) and memory citrulline-specific B-cells, which have been implicated in RA pathogenesis. While depletion of B-cells with Rituximab improves clinical responses in RA patients, this treatment strategy leaves patients susceptible to infections. Read More

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http://dx.doi.org/10.1021/acschembio.8b01018DOI Listing
March 2019
6 Reads

A High-Throughput Glycosyltransferase Inhibition Assay for Identifying Molecules Targeting Fucosylation in Cancer Cell-Surface Modification.

ACS Chem Biol 2019 Mar 14. Epub 2019 Mar 14.

Department of Chemistry and Biochemistry , National Chung-Cheng University , 168 University Road , Min-Hsiung , Chiayi 62102 , Taiwan.

In cancers, increased fucosylation (attachment of fucose sugar residues) on cell-surface glycans, resulting from the abnormal upregulation of the expression of specific fucosyltransferase enzymes (FUTs), is one of the most important types of glycan modifications associated with malignancy. Fucosylated glycans on cell surfaces are involved in a multitude of cellular interactions and signal regulation in normal biological processes, as well as in disease. For example, sialyl Lewis is a fucosylated cell-surface glycan that is abnormally abundant in some cancers where it has been implicated in facilitating metastasis, allowing circulating tumor cells to bind to the epithelial tissue within blood vessels and invade into secondary sites by taking advantage of glycan-mediated interactions. Read More

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http://dx.doi.org/10.1021/acschembio.8b01123DOI Listing

Molecular Basis of Bacillus subtilis ATCC 6633 Self-Resistance to the Phosphono-oligopeptide Antibiotic Rhizocticin.

ACS Chem Biol 2019 Mar 13. Epub 2019 Mar 13.

Carl R. Woese Institute for Genomic Biology , University of Illinois at Urbana-Champaign , 1206 W. Gregory Drive , Urbana , Illinois 61801 , United States.

Rhizocticins are phosphono-oligopeptide antibiotics that contain a toxic C-terminal ( Z) -l -2-amino-5-phosphono-3-pentenoic acid (APPA) moiety. APPA is an irreversible inhibitor of threonine synthase (ThrC), a pyridoxal 5'-phosphate (PLP)-dependent enzyme that catalyzes the conversion of O-phospho-l-homoserine to l-threonine. ThrCs are essential for the viability of bacteria, plants, and fungi and are a target for antibiotic development, as de novo threonine biosynthetic pathway is not found in humans. Read More

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http://dx.doi.org/10.1021/acschembio.9b00030DOI Listing
March 2019
1 Read

Esterification Delivers a Functional Enzyme into a Human Cell.

ACS Chem Biol 2019 Mar 11. Epub 2019 Mar 11.

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

A major hurdle in chemical biology is the delivery of native proteins into the cytosol of mammalian cells. Herein, we report that esterification of the carboxyl groups of an enzyme with a diazo compound enables not only its passage into the cytosol but also the retention of its catalytic activity there. This scenario is demonstrated with human ribonuclease 1, which manifests ribonucleolytic activity that can be cytotoxic. Read More

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http://dx.doi.org/10.1021/acschembio.9b00033DOI Listing

X-ray Crystal Structures of Short Antimicrobial Peptides as Pseudomonas aeruginosa Lectin B Complexes.

ACS Chem Biol 2019 Mar 11. Epub 2019 Mar 11.

Department of Chemistry and Biochemistry , University of Bern , Freiestrasse 3 , 3012 Bern , Switzerland.

Herein, we report X-ray crystal structures of 11-13 residue antimicrobial peptides (AMPs) active against Pseudomonas aeruginosa as complexes of fucosylated d-enantiomeric sequences with the P. aeruginosa lectin LecB. These represent the first crystal structures of short AMPs. Read More

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http://dx.doi.org/10.1021/acschembio.9b00047DOI Listing
March 2019
1 Read

Toward Single-Peak Dalbavancin Analogs through Biology and Chemistry.

ACS Chem Biol 2019 Mar 7;14(3):356-360. Epub 2019 Mar 7.

Naicons Srl , Viale Ortles 22/4 , 20139 Milano , Italy.

Glycopeptide antibiotics are used to treat severe multidrug resistant infections caused by Gram-positive bacteria. Dalbavancin is a second generation glycopeptide approved for human use, which is obtained from A40926, a lipoglycopeptide produced by Nonomuraea sp. ATCC39727 as a mixture of biologically active congeners mainly differing in the fatty acid chains present on the glucuronic moiety. Read More

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http://dx.doi.org/10.1021/acschembio.9b00050DOI Listing
March 2019
3 Reads

Bioactivity-HiTES Unveils Cryptic Antibiotics Encoded in Actinomycete Bacteria.

ACS Chem Biol 2019 Mar 19. Epub 2019 Mar 19.

Department of Chemistry , Princeton University , Princeton , New Jersey 08544 , United States.

Bacteria harbor an immense reservoir of potentially new and therapeutic small molecules in the form of "silent" biosynthetic gene clusters (BGCs). These BGCs can be identified bioinformatically but are sparingly expressed under normal laboratory growth conditions, or not at all, and therefore do not produce significant levels of the corresponding small molecule product. Several methods have been developed for activating silent BGCs. Read More

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http://dx.doi.org/10.1021/acschembio.9b00049DOI Listing
March 2019
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5.331 Impact Factor

Deconvoluting Stress-Responsive Proteostasis Signaling Pathways for Pharmacologic Activation Using Targeted RNA Sequencing.

ACS Chem Biol 2019 Mar 13. Epub 2019 Mar 13.

Department of Molecular Biosciences, Rice Institute for Biomedical Research , Northwestern University , Evanston , Illinois 60208 , United States.

Cellular proteostasis is maintained by stress-responsive signaling pathways such as the heat shock response (HSR), the oxidative stress response (OSR), and the unfolded protein response (UPR). Activation of these pathways results in the transcriptional upregulation of select subsets of stress-responsive genes that restore proteostasis and adapt cellular physiology to promote recovery following various types of acute insult. The capacity for these pathways to regulate cellular proteostasis makes them attractive therapeutic targets for correcting proteostasis defects associated with diverse diseases. Read More

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http://dx.doi.org/10.1021/acschembio.9b00134DOI Listing

Strategies for Generating Modified Nucleosomes: Applications within Structural Biology Studies.

ACS Chem Biol 2019 Mar 12. Epub 2019 Mar 12.

Department of Pharmacology , University of Colorado School of Medicine , Aurora , Colorado 80045 , United States.

Post-translational modifications on histone proteins play critical roles in the regulation of chromatin structure and all DNA-templated processes. Accumulating evidence suggests that these covalent modifications can directly alter chromatin structure, or they can modulate activities of chromatin-modifying and -remodeling factors. Studying these modifications in the context of the nucleosome, the basic subunit of chromatin, is thus of great interest; however, the generation of specifically modified nucleosomes remains challenging. Read More

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http://dx.doi.org/10.1021/acschembio.8b01049DOI Listing

An Oxidative Pathway for Microbial Utilization of Methylphosphonic Acid as a Phosphate Source.

ACS Chem Biol 2019 Mar 13. Epub 2019 Mar 13.

Department of Chemistry , Queen's University , Kingston , Ontario , Canada.

Methylphosphonic acid is synthesized by marine bacteria and is a prominent component of dissolved organic phosphorus. Consequently, methylphosphonic acid also serves as a source of inorganic phosphate (Pi) for marine bacteria that are starved of this nutrient. Conversion of methylphosphonic acid into Pi is currently only known to occur through the carbon-phosphorus lyase pathway, yielding methane as a byproduct. Read More

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http://dx.doi.org/10.1021/acschembio.9b00024DOI Listing
March 2019
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Multifunctionalization of Cells with a Self-Assembling Molecule to Enhance Cell Engraftment.

ACS Chem Biol 2019 Apr 5. Epub 2019 Apr 5.

Institute for Chemical Research , Kyoto University , Uji , Kyoto 611-0011 , Japan.

Cell-based therapy is a promising approach to restoring lost functions to compromised organs. However, the issue of inefficient cell engraftment remains to be resolved. Herein, we take a chemical approach to facilitate cell engraftment by using self-assembling molecules which modify two cellular traits: cell survival and invasiveness. Read More

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http://dx.doi.org/10.1021/acschembio.9b00109DOI Listing
April 2019
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A Phenotypic Screening Approach Using Human Treg Cells Identified Regulators of Forkhead Box p3 Expression.

ACS Chem Biol 2019 Mar 4;14(3):543-553. Epub 2019 Mar 4.

Target and Translational Science, Respiratory, Inflammation and Autoimmunity, IMED Biotech Unit, AstraZeneca, Gothenburg , 431 83 Mölndal Sweden.

Regulatory T (Treg) cells, expressing the transcription factor forkhead box p3 (FOXP3), are the key cells regulating peripheral autoreactive T lymphocytes by suppressing effector T cells. FOXP3 Treg cells play essential roles controlling immune responses in autoimmune diseases and cancer. Several clinical approaches (e. Read More

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http://dx.doi.org/10.1021/acschembio.9b00075DOI Listing

PROTAC-Mediated Degradation of Bruton's Tyrosine Kinase Is Inhibited by Covalent Binding.

ACS Chem Biol 2019 Mar 27;14(3):342-347. Epub 2019 Feb 27.

GSK Medicines Research Centre , Gunnels Wood Road , Stevenage SG1 2NY , U.K.

The impact of covalent binding on PROTAC-mediated degradation of BTK was investigated through the preparation of both covalent binding and reversible binding PROTACs derived from the covalent BTK inhibitor ibrutinib. It was determined that a covalent binding PROTAC inhibited BTK degradation despite evidence of target engagement, while BTK degradation was observed with a reversible binding PROTAC. These observations were consistently found when PROTACs that were able to recruit either IAP or cereblon E3 ligases were employed. Read More

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http://dx.doi.org/10.1021/acschembio.8b01094DOI Listing
March 2019
7 Reads