GNF-2 Inhibits Dengue Virus by Targeting Abl Kinases and the Viral E Protein.

Abstract:

:Dengue virus infects more than 300 million people annually, yet there is no widely protective vaccine or drugs against the virus. Efforts to develop antivirals against classical targets such as the viral protease and polymerase have not yielded drugs that have advanced to the clinic. Here, we show that the allosteric Abl kinase inhibitor GNF-2 interferes with dengue virus replication via activity mediated by cellular Abl kinases but additionally blocks viral entry via an Abl-independent mechanism. To characterize this newly discovered antiviral activity, we developed disubstituted pyrimidines that block dengue virus entry with structure-activity relationships distinct from those driving kinase inhibition. We demonstrate that biotin- and fluorophore-conjugated derivatives of GNF-2 interact with the dengue glycoprotein, E, in the pre-fusion conformation that exists on the virion surface, and that this interaction inhibits viral entry. This study establishes GNF-2 as an antiviral compound with polypharmacological activity and provides "lead" compounds for further optimization efforts.

journal_name

Cell Chem Biol

journal_title

Cell chemical biology

authors

Clark MJ,Miduturu C,Schmidt AG,Zhu X,Pitts JD,Wang J,Potisopon S,Zhang J,Wojciechowski A,Hann Chu JJ,Gray NS,Yang PL

doi

10.1016/j.chembiol.2016.03.010

subject

Has Abstract

pub_date

2016-04-21 00:00:00

pages

443-52

issue

4

eissn

2451-9456

issn

2451-9448

pii

S2451-9456(16)30088-5

journal_volume

23

pub_type

杂志文章
  • A Systems Chemoproteomic Analysis of Acyl-CoA/Protein Interaction Networks.

    abstract::Acyl-coenzyme A (CoA)/protein interactions are essential for life. Despite this importance, their global scope and selectivity remains undefined. Here, we describe CATNIP (CoA/AcetylTraNsferase Interaction Profiling), a chemoproteomic platform for the high-throughput analysis of acyl-CoA/protein interactions in endoge...

    journal_title:Cell chemical biology

    pub_type: 杂志文章

    doi:10.1016/j.chembiol.2019.11.011

    authors: Levy MJ,Montgomery DC,Sardiu ME,Montano JL,Bergholtz SE,Nance KD,Thorpe AL,Fox SD,Lin Q,Andresson T,Florens L,Washburn MP,Meier JL

    更新日期:2020-03-19 00:00:00

  • Unique Binding Specificities of Proteins toward Isomeric Asparagine-Linked Glycans.

    abstract::The glycan ligands recognized by Siglecs, influenza viruses, and galectins, as well as many plant lectins, are not well defined. To explore their binding to asparagine (Asn)-linked N-glycans, we synthesized a library of isomeric multiantennary N-glycans that vary in terminal non-reducing sialic acid, galactose, and N-...

    journal_title:Cell chemical biology

    pub_type: 杂志文章

    doi:10.1016/j.chembiol.2019.01.002

    authors: Gao C,Hanes MS,Byrd-Leotis LA,Wei M,Jia N,Kardish RJ,McKitrick TR,Steinhauer DA,Cummings RD

    更新日期:2019-04-18 00:00:00

  • Small-Molecule Kinase Downregulators.

    abstract::New opportunities to advance small-molecule kinase ligands that downregulate their cognate target binding proteins are discussed. Rationally designed heterobifunctional kinase degraders are compared with ATP site ligands that were serendipitously found to cause kinase downregulation. These approaches could be particul...

    journal_title:Cell chemical biology

    pub_type: 杂志文章,评审

    doi:10.1016/j.chembiol.2017.10.011

    authors: Jones LH

    更新日期:2018-01-18 00:00:00

  • USP7-Specific Inhibitors Target and Modify the Enzyme's Active Site via Distinct Chemical Mechanisms.

    abstract::USP7 is a deubiquitinating enzyme that plays a pivotal role in multiple oncogenic pathways and therefore is a desirable target for new anti-cancer therapies. However, the lack of structural information about the USP7-inhibitor interactions has been a critical gap in the development of potent inhibitors. USP7 is unique...

    journal_title:Cell chemical biology

    pub_type: 杂志文章

    doi:10.1016/j.chembiol.2017.09.004

    authors: Pozhidaeva A,Valles G,Wang F,Wu J,Sterner DE,Nguyen P,Weinstock J,Kumar KGS,Kanyo J,Wright D,Bezsonova I

    更新日期:2017-12-21 00:00:00

  • Discovery of an Inhibitor for Bacterial 3-Mercaptopyruvate Sulfurtransferase that Synergistically Controls Bacterial Survival.

    abstract::H2S-producing enzymes in bacteria have been shown to be closely engaged in the process of microbial survival and antibiotic resistance. However, no inhibitors have been discovered for these enzymes, e.g., 3-mercaptopyruvate sulfurtransferase (MST). In the present study, we identified several classes of inhibitors for ...

    journal_title:Cell chemical biology

    pub_type: 杂志文章

    doi:10.1016/j.chembiol.2020.10.012

    authors: Croppi G,Zhou Y,Yang R,Bian Y,Zhao M,Hu Y,Ruan BH,Yu J,Wu F

    更新日期:2020-12-17 00:00:00

  • Targeted Degradation of a Hypoxia-Associated Non-coding RNA Enhances the Selectivity of a Small Molecule Interacting with RNA.

    abstract::Small-molecule targeted recruitment of nucleases to RNA is a powerful method to affect RNA biology. Inforna, a sequence-based design approach to target RNA, enables the design of small molecules that bind to and cleave RNA in a selective and substoichiometric manner. Here, we investigate the ability of RNA-targeted de...

    journal_title:Cell chemical biology

    pub_type: 杂志文章

    doi:10.1016/j.chembiol.2019.04.008

    authors: Costales MG,Suresh B,Vishnu K,Disney MD

    更新日期:2019-08-15 00:00:00

  • Hit Triage and Validation in Phenotypic Screening: Considerations and Strategies.

    abstract::The promise of phenotypic screening resides in its track record of novel biology and first-in-class therapies. However, challenges stemming from major differences between target-based and phenotypic screening do exist. These challenges prompted us to rethink the critical stage of hit triage and validation on the road ...

    journal_title:Cell chemical biology

    pub_type: 杂志文章,评审

    doi:10.1016/j.chembiol.2020.08.009

    authors: Vincent F,Loria PM,Weston AD,Steppan CM,Doyonnas R,Wang YM,Rockwell KL,Peakman MC

    更新日期:2020-11-19 00:00:00

  • Small-Molecule-Targeting Hairpin Loop of hTERT Promoter G-Quadruplex Induces Cancer Cell Death.

    abstract::Increased telomerase activity is associated with malignancy and poor prognosis in human cancer, but the development of targeted agents has not yet provided clinical benefit. Here we report that, instead of targeting the telomerase enzyme directly, small molecules that bind to the G-hairpin of the hTERT G-quadruplex-fo...

    journal_title:Cell chemical biology

    pub_type: 杂志文章

    doi:10.1016/j.chembiol.2019.04.009

    authors: Song JH,Kang HJ,Luevano LA,Gokhale V,Wu K,Pandey R,Sherry Chow HH,Hurley LH,Kraft AS

    更新日期:2019-08-15 00:00:00

  • Small-Molecule Allosteric Triggers of Clostridium difficile Toxin B Auto-proteolysis as a Therapeutic Strategy.

    abstract::Clostridium difficile causes increasing numbers of life-threatening intestinal infections. Symptoms associated with C. difficile infection (CDI) are mediated by secreted protein toxins, whose virulence is modulated by intracellular auto-proteolysis following allosteric activation of their protease domains by inositol ...

    journal_title:Cell chemical biology

    pub_type: 杂志文章

    doi:10.1016/j.chembiol.2018.10.002

    authors: Ivarsson ME,Durantie E,Huberli C,Huwiler S,Hegde C,Friedman J,Altamura F,Lu J,Verdu EF,Bercik P,Logan SM,Chen W,Leroux JC,Castagner B

    更新日期:2019-01-17 00:00:00

  • Lanthanide-Based Optical Probes of Biological Systems.

    abstract::The unique photophysical properties of lanthanides, such as europium, terbium, and ytterbium, make them versatile molecular probes of biological systems. In particular, their long-lived photoluminescence, narrow bandwidth emissions, and large Stokes shifts enable experiments that are infeasible with organic fluorophor...

    journal_title:Cell chemical biology

    pub_type: 杂志文章,评审

    doi:10.1016/j.chembiol.2020.07.009

    authors: Cho U,Chen JK

    更新日期:2020-08-20 00:00:00

  • BMPing Up Healing Capacity with FKBP12 Ligand.

    abstract::While the wound healing property of the macrolide FK506 is well known, the underlying mechanism has been elusive. In this issue of Cell Chemical Biology, Peiffer et al. (2019) utilize FKBP12 ligand to demonstrate that wound healing effects of FK506 occur via activation of the BMP (bone morphogenic protein) signaling p...

    journal_title:Cell chemical biology

    pub_type: 评论,杂志文章

    doi:10.1016/j.chembiol.2019.05.001

    authors: Williams CH,Hong CC

    更新日期:2019-05-16 00:00:00

  • "Expand and Click": A New Method for Labeling HIV-1 Envelope Glycoproteins.

    abstract::In this issue of Cell Chemical Biology, Sakin et al. (2017) investigate the nanoscale behavior of the HIV-1 envelope (Env) glycoprotein complex by using genetic code expansion, bioorthogonal amino acids, synthetic dyes, and click chemistry. This minimally invasive approach allows the measurement of native Env cellular...

    journal_title:Cell chemical biology

    pub_type: 杂志文章

    doi:10.1016/j.chembiol.2017.05.006

    authors: Fernandez MV,Freed EO

    更新日期:2017-05-18 00:00:00

  • Rox, a Rifamycin Resistance Enzyme with an Unprecedented Mechanism of Action.

    abstract::Rifamycin monooxygenases (Rox) are present in a variety of environmental bacteria and are associated with decomposition of the clinically utilized antibiotic rifampin. Here we report the structure and function of a drug-inducible rox gene from Streptomyces venezuelae, which encodes a class A flavoprotein monooxygenase...

    journal_title:Cell chemical biology

    pub_type: 杂志文章

    doi:10.1016/j.chembiol.2018.01.009

    authors: Koteva K,Cox G,Kelso JK,Surette MD,Zubyk HL,Ejim L,Stogios P,Savchenko A,Sørensen D,Wright GD

    更新日期:2018-04-19 00:00:00

  • Posttranslational Peptide-Modification Enzymes in Action: Key Roles for Leaders and Glutamate.

    abstract::In this issue of Cell Chemical Biology, Ortega et al. (2016) determine the structure of another lantibiotic dehydratase with a tRNA(Glu)-dependent mechanism of modification. Moreover, they identify a common recognition motif involved in leader peptide binding in a number of different peptide-modification enzymes. Thes...

    journal_title:Cell chemical biology

    pub_type: 评论,杂志文章

    doi:10.1016/j.chembiol.2016.03.001

    authors: Montalbán-López M,Kuipers OP

    更新日期:2016-03-17 00:00:00

  • AKAP95 Organizes a Nuclear Microdomain to Control Local cAMP for Regulating Nuclear PKA.

    abstract::Contrary to the classic model of protein kinase A (PKA) residing outside of the nucleus, we identify a nuclear signaling complex that consists of AKAP95, PKA, and PDE4D5 and show that it forms a functional cyclic AMP (cAMP) signaling microdomain. Locally generated cAMP can accumulate within the vicinity of this comple...

    journal_title:Cell chemical biology

    pub_type: 杂志文章

    doi:10.1016/j.chembiol.2019.03.003

    authors: Clister T,Greenwald EC,Baillie GS,Zhang J

    更新日期:2019-06-20 00:00:00

  • Hypomorph Mutation-Directed Small-Molecule Protein-Protein Interaction Inducers to Restore Mutant SMAD4-Suppressed TGF-β Signaling.

    abstract::Tumor suppressor genes represent a major class of oncogenic drivers. However, direct targeting of loss-of-function tumor suppressors remains challenging. To address this gap, we explored a variant-directed chemical biology approach to reverse the lost function of tumor suppressors using SMAD4 as an example. SMAD4, a c...

    journal_title:Cell chemical biology

    pub_type: 杂志文章

    doi:10.1016/j.chembiol.2020.11.010

    authors: Tang C,Mo X,Niu Q,Wahafu A,Yang X,Qui M,Ivanov AA,Du Y,Fu H

    更新日期:2020-12-04 00:00:00

  • Discovery of an Unnatural DNA Modification Derived from a Natural Secondary Metabolite.

    abstract::Despite widespread interest for understanding how modified bases have evolved their contemporary functions, limited experimental evidence exists for measuring how close an organism is to accidentally creating a new, modified base within the framework of its existing genome. Here, we describe the biochemical and struct...

    journal_title:Cell chemical biology

    pub_type: 杂志文章

    doi:10.1016/j.chembiol.2020.09.006

    authors: Wang T,Kohli RM

    更新日期:2021-01-21 00:00:00

  • A Ratiometric Sensor for Imaging Insulin Secretion in Single β Cells.

    abstract::Despite the urgent need for assays to visualize insulin secretion there is to date no reliable method available for measuring insulin release from single cells. To address this need, we developed a genetically encoded reporter termed RINS1 based on proinsulin superfolder GFP (sfGFP) and mCherry fusions for monitoring ...

    journal_title:Cell chemical biology

    pub_type: 杂志文章

    doi:10.1016/j.chembiol.2017.03.001

    authors: Schifferer M,Yushchenko DA,Stein F,Bolbat A,Schultz C

    更新日期:2017-04-20 00:00:00

  • Robust Prediction of Resistance to Trimethoprim in Staphylococcus aureus.

    abstract::The rise of antibiotic resistance threatens modern medicine; to combat it new diagnostic methods are required. Sequencing the whole genome of a pathogen offers the potential to accurately determine which antibiotics will be effective to treat a patient. A key limitation of this approach is that it cannot classify rare...

    journal_title:Cell chemical biology

    pub_type: 杂志文章

    doi:10.1016/j.chembiol.2017.12.009

    authors: Fowler PW,Cole K,Gordon NC,Kearns AM,Llewelyn MJ,Peto TEA,Crook DW,Walker AS

    更新日期:2018-03-15 00:00:00

  • Customizing Functionalized Cofactor Mimics to Study the Human Pyridoxal 5'-Phosphate-Binding Proteome.

    abstract::Pyridoxal 5'-phosphate (PLP) is a versatile cofactor that catalyzes a plethora of chemical transformations within a cell. Although many human PLP-dependent enzymes (PLP-DEs) with crucial physiological and pathological roles are known, a global method enabling their cellular profiling is lacking. Here, we demonstrate t...

    journal_title:Cell chemical biology

    pub_type: 杂志文章

    doi:10.1016/j.chembiol.2019.08.003

    authors: Fux A,Pfanzelt M,Kirsch VC,Hoegl A,Sieber SA

    更新日期:2019-10-17 00:00:00

  • A Genetic Toggle for Chemical Control of Individual Plk1 Substrates.

    abstract::Polo-like kinase 1 has hundreds of substrates and multiple functions that operate within the ∼60 min of mitosis. Herein, we describe a chemical-genetic system that allows particular substrates to be "toggled" into or out of chemical control using engineered phosphoacceptor selectivity. Biochemical assays and phosphopr...

    journal_title:Cell chemical biology

    pub_type: 杂志文章

    doi:10.1016/j.chembiol.2020.01.007

    authors: Johnson JM,Hebert AS,Drane QH,Lera RF,Wan J,Weaver BA,Coon JJ,Burkard ME

    更新日期:2020-03-19 00:00:00

  • Dawn of a New Era of Targeted Antioxidant Therapies.

    abstract::In this issue of Cell Chemical Biology, Shah et al. (2019) report an in vitro, high-throughput assay that predicts the ability of compounds to suppress peroxidation of phospholipids. This approach provides a way to design and optimize targeted antioxidants that suppress specific oxidative event in cells, potentially o...

    journal_title:Cell chemical biology

    pub_type: 评论,杂志文章

    doi:10.1016/j.chembiol.2019.11.003

    authors: Stockwell BR

    更新日期:2019-11-21 00:00:00

  • The High Genetic Barrier of EFdA/MK-8591 Stems from Strong Interactions with the Active Site of Drug-Resistant HIV-1 Reverse Transcriptase.

    abstract::4'-Ethynyl-2-fluoro-2'-deoxyadenosine (EFdA/MK-8591), a nucleoside reverse transcriptase inhibitor (NRTI) under clinical trials, is a potent and promising long-acting anti-HIV type 1 (HIV-1) agent. EFdA and its derivatives possess a modified 4'-moiety and potently inhibit the replication of a wide spectrum of HIV-1 st...

    journal_title:Cell chemical biology

    pub_type: 杂志文章

    doi:10.1016/j.chembiol.2018.07.014

    authors: Takamatsu Y,Das D,Kohgo S,Hayashi H,Delino NS,Sarafianos SG,Mitsuya H,Maeda K

    更新日期:2018-10-18 00:00:00

  • Light-Activated Chemotaxis.

    abstract::Using light to control cellular processes is one of the attractive areas of research. Here, availability of different, light-responsive caged compounds has played a critical role. In this issue of Cell Chemical Biology, Hövelmann et al. (2016) give us an example of how to design and use caged lipids to guide chemotaxi...

    journal_title:Cell chemical biology

    pub_type: 评论,杂志文章

    doi:10.1016/j.chembiol.2016.05.003

    authors: Dore TM

    更新日期:2016-05-19 00:00:00

  • Combined Proteomic and In Silico Target Identification Reveal a Role for 5-Lipoxygenase in Developmental Signaling Pathways.

    abstract::Identification and validation of the targets of bioactive small molecules identified in cell-based screening is challenging and often meets with failure, calling for the development of new methodology. We demonstrate that a combination of chemical proteomics with in silico target prediction employing the SPiDER method...

    journal_title:Cell chemical biology

    pub_type: 杂志文章

    doi:10.1016/j.chembiol.2018.05.016

    authors: Brand S,Roy S,Schröder P,Rathmer B,Roos J,Kapoor S,Patil S,Pommerenke C,Maier T,Janning P,Eberth S,Steinhilber D,Schade D,Schneider G,Kumar K,Ziegler S,Waldmann H

    更新日期:2018-09-20 00:00:00

  • Privileged Electrophile Sensors: A Resource for Covalent Drug Development.

    abstract::This Perspective delineates how redox signaling affects the activity of specific enzyme isoforms and how this property may be harnessed for rational drug design. Covalent drugs have resurged in recent years and several reports have extolled the general virtues of developing irreversible inhibitors. Indeed, many modern...

    journal_title:Cell chemical biology

    pub_type: 杂志文章,评审

    doi:10.1016/j.chembiol.2017.05.023

    authors: Long MJC,Aye Y

    更新日期:2017-07-20 00:00:00

  • A ZDHHC5-GOLGA7 Protein Acyltransferase Complex Promotes Nonapoptotic Cell Death.

    abstract::Lethal small molecules are useful probes to discover and characterize novel cell death pathways and biochemical mechanisms. Here we report that the synthetic oxime-containing small molecule caspase-independent lethal 56 (CIL56) induces an unconventional form of nonapoptotic cell death distinct from necroptosis, ferrop...

    journal_title:Cell chemical biology

    pub_type: 杂志文章

    doi:10.1016/j.chembiol.2019.09.014

    authors: Ko PJ,Woodrow C,Dubreuil MM,Martin BR,Skouta R,Bassik MC,Dixon SJ

    更新日期:2019-12-19 00:00:00

  • Catching Sirtuin-2 Intermediates One Structure at the Time.

    abstract::Sirtuins are a large enzyme family involved in installing and removing post-translational modifications involving lysine side chains. These enzymes have been of intense research interest and we now understand many details of their mechanism, although later steps of the deacetylase activity have remained a mystery. In ...

    journal_title:Cell chemical biology

    pub_type: 评论,杂志文章

    doi:10.1016/j.chembiol.2017.03.004

    authors: Lee S,Chen Z,Zhang G

    更新日期:2017-03-16 00:00:00

  • BLISS: A Bioorthogonal Dual-Labeling Strategy to Unravel Lignification Dynamics in Plants.

    abstract::A better in vivo understanding of lignin formation within plant cell walls will contribute to improving the valorization of plant-derived biomass. Although bioorthogonal chemistry provides a promising platform to study the lignification process, methodologies that simultaneously detect multiple chemical reporters in l...

    journal_title:Cell chemical biology

    pub_type: 杂志文章

    doi:10.1016/j.chembiol.2017.02.009

    authors: Lion C,Simon C,Huss B,Blervacq AS,Tirot L,Toybou D,Spriet C,Slomianny C,Guerardel Y,Hawkins S,Biot C

    更新日期:2017-03-16 00:00:00

  • Conformation Selective Antibody Enables Genome Profiling and Leads to Discovery of Parallel G-Quadruplex in Human Telomeres.

    abstract::G-quadruplexes are specialized secondary structures in nucleic acids that possess significant conformational polymorphisms. The precise G-quadruplex conformations in vivo and their relevance to biological functions remain controversial and unclear, especially for telomeric G-quadruplexes. Here, we report a novel singl...

    journal_title:Cell chemical biology

    pub_type: 杂志文章

    doi:10.1016/j.chembiol.2016.08.013

    authors: Liu HY,Zhao Q,Zhang TP,Wu Y,Xiong YX,Wang SK,Ge YL,He JH,Lv P,Ou TM,Tan JH,Li D,Gu LQ,Ren J,Zhao Y,Huang ZS

    更新日期:2016-10-20 00:00:00