Identification of exosite-targeting inhibitors of anthrax lethal factor by high-throughput screening

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Highlights? Development of an assay for LF protease using a full-length protein substrate ? Lichen depsidones identified as exosite-targeting LF inhibitors ? Exosite inhibitors protect macrophages from LF cytotoxicity     

Validation of the Proteasome as a Therapeutic Target in Plasmodium Using an Epoxyketone Inhibitor with Parasite-Specific Toxicity

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Highlights? Purification of Plasmodium proteasomes and labeling with an activity-based probe ? Identification of an epoxyketone-based inhibitor with parasite-specific toxicity ? Demonstration that Plasmodium is sensitive to partial inhibition of its proteasome ? Determination of key parameters for selective parasite killing with proteasome inhibitors     

Terpendole E,a Kinesin Eg5 Inhibitor,Is a Key Biosynthetic Intermediate of Indole-Diterpenes in the Producing Fungus Chaunopycnis alba

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Highlights? The terpendole biosynthetic gene cluster was isolated ? Terpendole E is a key biosynthetic intermediate of indole-diterpenes ? Terpendole E was overproduced by gene knockout of the bispecific enzyme TerP ? Indole-diterpene biosynthetic pathways can be classified into two groups     

A Yeast Chemical Genetic Screen Identifies Inhibitors of Human Telomerase

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Highlights? Growth arrest induced by human telomerase in yeast is chemically reversible ? Readout is sensitive to telomerase catalytic activity and telomere recruitment ? Three cell-permeable compounds also inhibit purified human telomerase ? Yeast can be successfully used to screen for human telomerase inhibitors     

BTZO-1, a cardioprotective agent, reveals that macrophage migration inhibitory factor regulates ARE-mediated gene expression

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Highlights? ARE activation is involved in cellular protection against oxidative stress ? MIF is a ubiquitous protein with conserved nucleophilic Pro1 in a hydrophobic pocket ? BTZO-1 selectively binds to MIF, and its binding required the intact N-terminal Pro1 ? Binding of BTZO-1 to MIF leads to the ARE activation in cardiomyocytes.     

A Synthetic Substrate of DNA Polymerase Deviating from the Bases,Sugar, and Leaving Group of Canonical Deoxynucleoside Triphosphates

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Highlights? A highly modified nucleotide as substrate for polymerases ? The reversibility of the polymerase reaction at the template level ? Synthesis of a nucleoside with two anomeric centers     

Synthetically accessible non-secosteroidal hybrid molecules combining vitamin d receptor agonism and histone deacetylase inhibition

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Highlights? Synthetically accessible hybrids of 1,25D and HDACi are created ? Hybrids with hydroxamic acids in the A-ring binding pocket are active as VDR agonists ? Hybrids are potent inhibitors of 1,25D-sensitive and 1,25D-resistant cancer cell growth     

Effector Kinase Coupling Enables High-Throughput Screens for Direct HIV-1 Nef Antagonists with Antiretroviral Activity

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Highlights? Nef is a critical HIV virulence factor lacking biochemical activity amenable to HTS ? HTS for inhibitors of Nef-mediated Hck kinase activation identified Nef antagonists ? Hit compound B9 blocks Nef-dependent HIV replication with submicromolar potency ? B9 binds directly to purified HIV Nef in vitro and blocks Nef dimerization in cells     

Discovery of potent and selective covalent inhibitors of JNK

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Highlights? JNK inhibitors have been designed that target a conserved cysteine residue ? JNK-IN-8 is a highly selective JNK inhibitor based on multiple profiling strategies ? Covalent formation is crucial for both high potency and high specificity ? JNK-IN-8 inhibits c-Jun phosphorylation at submicromolar concentrations in cells     

Specific Small Molecule Inhibitors of Skp2-Mediated p27 Degradation

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Highlights? In silico screening against a pocket formed by the Skp2-Cks1 protein interface ? Structure-based discovery of Skp2 ligase inhibitors that block p27 ubiquitylation ? Inhibition of Skp2 ligase activity stabilizes p27 protein in melanoma cells ? Inhibitor induction of p27 results in cell cycle arrest in various cancer cells     

An integrated chemical biology approach provides insight into cdk2 functional redundancy and inhibitor sensitivity

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Highlights? Demonstration that Cdk2 is rate-limiting for DNA replication due to insufficient Cdk1 activity ? A simple bioinformatic approach to design inhibitor resistant mutations in kinases ? Demonstration of distinct binding modes and selectivity of Cdk inhibitors ? Identification of kinetic and structural mechanisms of inhibitor resistance     

Engineering the Substrate Specificity of the DhbE Adenylation Domain by Yeast Cell Surface Display

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Highlights? Yeast surface display to engineer substrate recognition of adenylation (A) domains ? Synthesis of bisubstrate inhibitors for yeast selection of A domain library ? Identifying DhbE mutants specific for 3-hydroxybenzoic acid and 2-aminobenzoic acid ? Key residues in A domain for substrate recognition and transfer     

Dissecting Fragment-Based Lead Discovery at the von Hippel-Lindau Protein:Hypoxia Inducible Factor 1α Protein-Protein Interface

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Highlights? Inhibitors of pVHL:HIF-1α interaction are ligand-efficient and retain binding mode ? Ro3-compliant fragments of these inhibitors are not hits in biophysical screens ? Successful hit fragments break the Ro3 and target at least two subsites at the PPI ? Integration of GE and GLE analyses provide methodology to probe hot spots at a PPI     

Discovery of an Iron-Regulated Citrate Synthase in Staphylococcus aureus

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Highlights? Staphylococcus aureus SbnG is discovered to be an iron-regulated citrate synthase ? SbnG provides citrate for synthesis of the citrate siderophore staphyloferrin B ? Staphyloferrin B can be synthesized in vitro using purified enzymes ? SbnG inhibitors identified     

Interplay between the Ribosomal Tunnel,Nascent Chain,and Macrolides Influences Drug Inhibition

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Highlights? Macrolides exhibit nascent polypeptide chain–dependent inhibition ? Peptides can form specific interactions with the ribosomal tunnel ? A covalent bond between tylosin and the ribosome is necessary for inhibitory activity     

Morphobase,an Encyclopedic Cell Morphology Database,and Its Use for Drug Target Identification

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Highlights? Development of an encyclopedia of cell morphology, Morphobase ? Small molecules classified by mode of action with Morphobase ? Morphobase system rapidly predicts molecular targets of compounds ? NPD6689 targets tubulin and is a lead for a class of antitubulin drugs     

ALDH2 Mediates 5-Nitrofuran Activity in Multiple Species

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Highlights? Zebrafish provide a viable assay for the biological toxicity of 5-nitrofurans ? ALDH2 inhibitors prevent 5-nitrofuran toxicity in zebrafish and yeast ? Genetic dependence on ALDH2 for 5-nitrofuran toxicity in zebrafish and yeast systems ? 5-Nitrofurans bind to and are substrates of human ALDH2     

Reconstitution of Nucleosome Demethylation and Catalytic Properties of a Jumonji Histone Demethylase

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Highlights? Catalytic domain of JMJD2A (cJMJD2A) removes methyl marks in a distributive manner ? Homogeneously methylated nucleosomes were used as substrates ? Quantitative assay for nucleosome demethylation has been developed     

A Substrate-Inspired Probe Monitors Translocation,Activation, and Subcellular Targeting of Bacterial Type III Effector Protease AvrPphB

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Highlights? Bacterial papain-like protease AvrPphB cleaves kinases in host plant cell ? Activity-based probe for AvrPphB inspired on its unique substrate specificity ? Secretion of ProAvrPphB through narrow type III pilus requires prodomain ? Prodomain removal is essential to trigger cell death in resistant plants