CXCR4 Stimulates Macropinocytosis: Implications for Cellular Uptake of Arginine-Rich Cell-Penetrating Peptides and HIV

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Highlights? CXCR4 was identified as a receptor to stimulate cellular uptake of R12 peptide ? Interaction with R12 stimulates internalization of CXCR4 via macropinocytosis ? SDF-1α and HIV-1 gp120 protein also induce macropinocytosis ? Macropinocytic uptake of HIV-1 diminished the infection of host cells     

AMP-Activated Protein Kinase: A Target for Drugs both Ancient and Modern

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Highlights? AMP-activated protein kinase (AMPK) is a sensor of cellular energy status ? Drugs that activate AMPK have potential in type 2 diabetes and in cancer ? Many existing drugs and xenobiotics (e.g., metformin, salicylate) activate AMPK ? Most, but not all, AMPK-activating xenobiotics inhibit mitochondrial function     

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     

The Antimalarial Natural Product Symplostatin 4 Is a Nanomolar Inhibitor of the Food Vacuole Falcipains

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Highlights? A convergent chemical synthesis of symplostatin 4 (Sym4) and Sym4 derivatives is reported ? Sym4 irreversibly inhibits malarial falcipains in infected red blood cells ? Sym4's unusual methyl-methoxypyrrolinone group is required for nanomolar inhibition of falcipains     

Synthesis and Screening of Stereochemically Diverse Combinatorial Libraries of Peptide Tertiary Amides

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Highlights? A convenient synthesis of libraries of conformationally-constrained N-substituted oligoalanines ? A screen of such a library provided much higher affinity hits than a library of peptoids lacking c-alpha substitution ? Analysis of the isolated protein ligands demonstrated that the stereochemistry of the chiral centers was important ? These libraries should be a useful source of high affinity protein ligands     

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     

Development of Antibiotic Activity Profile Screening for the Classification and Discovery of Natural Product Antibiotics

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Highlights? Antibiotics can be classified by structural class based on biological fingerprints ? BioMAP predicts the presence of known compounds in natural product extracts ? BioMAP reveals compounds with unique antibacterial properties ? A naphthoquinone antibiotic with a unique carbon skeleton has been discovered     

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.     

Discovery of Peptoid Ligands for Anti-Aquaporin 4 Antibodies

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Highlights? Peptoid ligands for anti-AQP4 autoantibodies that drive NMO have been identified ? Some of these peptoids provide an accurate blood test for the disease     

Design and Application of In Vivo FRET Biosensors to Identify Protein Prenylation and Nanoclustering Inhibitors

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Highlights? Cellular FRET biosensors for Ras, Rho, and Rab membrane anchorage were developed ? We provide evidence for Rab protein nanoclustering on cellular membranes ? Two FRET biosensors were demonstrated to be suitable for high-throughput screening ? Macrotetrolides were identified as nanoclustering and MAPK signaling disruptors     

Rational design of an aryl-C-glycoside catalyst from a natural product O-glycosyltransferase

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Highlights? 106 rationally designed chimeras were expressed in vivo and screened by HPLC-MS analysis ? One 12-amino acid protein segment is crucial for O- or C-glycosylation ? The sugar-acceptor postioning determines O- or C-glycosidic bond formation ? Ala substitutions revealed the key spots for glycosylation     

Regulation of Telomere Length by G-Quadruplex Telomere DNA- and TERRA-Binding Protein TLS/FUS

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Highlights? TLS/FUS is identified as a G-quadruplex telomere DNA and TERRA-binding protein ? TLS binds to G-quadruplex telomere DNA and TERRA simultaneously ? The cells overexpressing TLS show gradual and progressive telomere shortening ? Overexpression of TLS results in trimethylation of histone H3 and H4 at telomere     

HTS by NMR of Combinatorial Libraries: A Fragment-Based Approach to Ligand Discovery

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Highlights? HTS by NMR combines protein NMR and combinatorial chemistry to screen large libraries ? The approach is best suited to identify ligands to protein-protein interactions ? The method enables a rapid assessment of the druggability of a given target ? We applied the method to a test case and to derive potent and selective EphA4 ligands     

Picoliter cell lysate assays in microfluidic droplet compartments for directed enzyme evolution

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Highlights? Microfluidic droplet compartments miniaturize cell lysate screening assays ? Picoliter single-cell lysate assays comparable in sensitivity to macroscale ? Directed evolution results in improved clones validating this experimental set-up ? Precision of droplet sorting enables enrichment of clones with slight improvements     

A Bacterial Source for Mollusk Pyrone Polyketides

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Highlights? Symbiotic bacteria synthesize compounds found in mollusks ? Physically defended mollusks provide a source for bioactive metabolite discovery ? A type of pyrone polyketide pathway described ? Nocardiopsis strains may be widespread, casually associated symbionts of inveterbrates     

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     

Biosynthetic Conclusions from the Functional Dissection of Oxygenases for Biosynthesis of Actinorhodin and Related Streptomyces Antibiotics

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Highlights? ActVA-ORF5 is a flavin-dependent monooxygenase required for actinorhodin biosynthesis ? ActVA-ORF5 and its three close homologs were functionally dissected ? ActVA-ORF5 and Gra-21 are bifunctional at C-6/C-8, while Med-7 acts only for C-6 ? AlnT exhibits different regiospecificity for oxidation of tricyclic substrates     

Codon Randomization for Rapid Exploration of Chemical Space in Thiopeptide Antibiotic Variants

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Highlights? Thiopeptide GE37468 expression was increased 30-fold above previous reports ? Codon randomization enabled rapid exploration of chemical space ? Thirteen thiopeptide analogs had activity against MRSA ? Identification of linear precursor peptides allowed insights into biosynthetic timing     

Orthogonal Ubiquitin Transfer through Engineered E1-E2 Cascades for Protein Ubiquitination

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Highlights? Orthogonal ubiquitin (UB) transfer pathway to synthesize specific UB-E2 conjugates ? Phage display to engineer UB-E1 and UB-E2 interactions ? Engineered xUB-xE1 and xE1-xE2 pairs with no cross-reactivities with native enzymes     

Directed Evolution of a Soluble Human IL-17A Receptor for the Inhibition of Psoriasis Plaque Formation in a Mouse Model

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Highlights? IL-17 is involved in many inflammatory diseases ? Directed evolution of IL-17A receptor results in improved IL-17A affinity ? The engineered receptors efficiently inhibit IL-17A induced cytokine secretion ? Engineered receptor promotes the recovery of psoriasis plaques in mouse model