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Showing papers in "Chemistry & Biology in 2015"


Journal ArticleDOI
TL;DR: ARV-825 is designed, a hetero-bifunctional PROTAC (Proteolysis Targeting Chimera) that recruits BRD4 to the E3 ubiquitin ligase cereblon, leading to fast, efficient, and prolonged degradation ofBRD4 in all BL cell lines tested.

791 citations


Journal ArticleDOI
TL;DR: A light-inducible, user-defined, endogenous gene activation system based on CRISPR-Cas9 that can allow rapid and reversible targeted gene activation by light and exemplified photoactivation of multiple user- defined endogenous genes in mammalian cells is created.

277 citations


Journal ArticleDOI
TL;DR: Specific D-enantiomeric peptides were the most potent at inhibiting biofilm development and eradicating preformed biofilms of seven species of wild-type and multiply antibiotic-resistant Gram-negative pathogens.

256 citations


Journal ArticleDOI
TL;DR: The crystal structures of representative β-glucuronidases from the Firmicutes Streptococcus agalactiae and Clostridium perfringens and the Proteobacterium Escherichia coli are reported and it is established that β- glucuronidsase inhibition does not alter the serum pharmacokinetics of irinotecan or its metabolites in mice.

186 citations


Journal ArticleDOI
TL;DR: The importance of targeting D SB repair pathways for the treatment of cancer is discussed and recent advances in the development of DSB repair inhibitors and their clinical relevance are addressed.

175 citations


Journal ArticleDOI
TL;DR: Molecular networking and the new concept of pattern-based genome mining are applied to 35 Salinispora strains to provide a method to simultaneously compare large numbers of complex microbial extracts, which facilitated the identification of media components, known compounds and their derivatives, and new compounds that could be prioritized for structure elucidation.

152 citations


Journal ArticleDOI
TL;DR: This review highlights examples of G-quadruplex probes that have been reported over the last few years, some of which have been employed for cellular imaging or for use in the construction ofG- quadruplex-based analytical sensing platforms.

150 citations


Journal ArticleDOI
TL;DR: A family of flavoenzymes, previously unrecognizable as resistance genes, which are capable of degrading tetracycline antibiotics are described, and it is demonstrated that a tenth enzyme, an uncharacterized homolog in the human pathogen Legionella longbeachae, similarly inactivates tetrACYcline.

138 citations


Journal ArticleDOI
TL;DR: Methods for screening RNA cleavage events in cells and identify cell-compatible scaffolds that enable efficient tagging of RNAs with aptamers for cellular expression are described.

135 citations


Journal ArticleDOI
TL;DR: This article focuses on the specific challenges of developing PPI inhibitors and detail the recent advances in chemistry, biology, and computation that facilitate overcoming them and outlines four innovations that are seen as key enabling steps for successful development of small-molecule inhibitors targeting PPIs.

129 citations


Journal ArticleDOI
TL;DR: The ability of Hsp27 to prevent amorphous or fibrillar aggregation of target proteins was enhanced and correlated with the amount of dissociated species present, and proposed that, in vivo, phosphorylation promotes oligomer dissociation, thereby enhancing chaperone activity.

Journal ArticleDOI
TL;DR: Using CRISPR/Cas9 genome editing, it is shown that a homozygous genomic C528S mutation in the XPO1 gene confers cells with resistance to selinexor (KPT-330), validating XPo1 as the prime target of selineXor in cells and identifying the selectivity of this drug toward the cysteine 528 residue of XPO 1.

Journal ArticleDOI
TL;DR: The pathways that enable incorporation of tryptophan into complex metabolites in bacteria are reviewed, with a focus on recently discovered, unusual metabolic transformations.

Journal ArticleDOI
TL;DR: A comprehensive survey uncovered clustering of modifications within biologically related protein networks, providing the first evidence for the occurrence of distinct, endogenous protein networks that undergo redox signaling through specific cysteine modifications.

Journal ArticleDOI
TL;DR: The crystal structures reveal the binding modes of these molecules that compete against H3K27me3 binding through interactions with key residues in the methyl-lysine binding pocket of CBX7ChD, and show that a lead compound, MS37452, derepresses transcription of Polycomb repressive complex target gene p16/CDKN2A by displacing CBx7 binding to the INK4A/ARF locus in prostate cancer cells.

Journal ArticleDOI
TL;DR: A potential K(+) ion-dependent equilibrium between GQ and the stem-loop structure has the ability to regulate the Dicer-mediated maturation of pre-miRNA 92b, which consequently affects target gene silencing.

Journal ArticleDOI
TL;DR: Using an unbiased chemical crosslinking/mass spectrometry approach, interspecies protein-protein interactions in human lung epithelial cells infected with Acinetobacter baumannii are identified and the key A. baumannii virulence factor, OmpA, was identified as crosslinked to host proteins involved in desmosomes, specialized structures that mediate host cell-to-cell adhesion.

Journal ArticleDOI
TL;DR: It is observed that cellular RIPK2 can be potently inhibited by type II inhibitors that displace the kinase activation segment, whereas ATP-competitive type I inhibition was only poorly effective.

Journal ArticleDOI
TL;DR: The data suggest that PqsE promotes the efficiency of alkylquinolone signal molecule biosynthesis in P. aeruginosa and balances the levels of secondary metabolites deriving from the alkylbenzoylacetyl-coenzyme A biosynthesis pathway.

Journal ArticleDOI
TL;DR: The cloning of a biosynthetic gene and characterization of the corresponding enzyme that acts at this crucial branchpoint, which converts strictosidine aglycone to the heteroyohimbine-type alkaloid tetrahydroalstonine are reported for the first time.

Journal ArticleDOI
TL;DR: An optogenetic strategy to control the transport and distribution of organelles by light is reported, which demonstrates that mitochondria, peroxisomes, and lysosomes can be driven toward the cell periphery upon light-induced recruitment of kinesin, or toward thecell nucleus upon recruitment of dynein.

Journal ArticleDOI
TL;DR: An in situ assay is developed and used to demonstrate that SFTI-1 is excised and simultaneously macrocyclized from its linear precursor to propose that the evolution of ligating endoproteases enables plants like sunflower and jack bean to stabilize bioactive peptides.

Journal ArticleDOI
TL;DR: The results suggest that subdomain swapping could be a viable alternative to previous NRPS design approaches targeting binding pockets, domains, or entire modules and the short length of the swapped sequence stretch may facilitate straightforward exploitation of the wealth of existing NRPS modules for combinatorial biosynthesis.

Journal ArticleDOI
TL;DR: Animal studies indicate that apoptozole treatment retards tumor growth in a xenograft mouse model without affecting mouse viability and suggest that Az will aid the development of new cancer therapies and serve as a chemical probe to gain a better understanding of the diverse functions of HSP70.

Journal ArticleDOI
TL;DR: Conditional depletion of the essential thymidylate synthase ThyX resulted in modest hypersensitivity to 5-FU, implicating inhibition of ThyX by fluorodeoxyuridylates as a further component of the mechanism of antimycobacterial action of this drug.

Journal ArticleDOI
TL;DR: The results reveal that activation of cardiolipin synthesis and remodeling supports mitochondrial biogenesis in the transition from fermentative to respiratory metabolism, and that endogenous synthesis of unsaturated fatty acids constitutes an in vivo upstream activator of peroxisomal biogenesis, via the heterodimeric Oaf1/Pip2 transcription factor.

Journal ArticleDOI
TL;DR: 6-OH-dopa selectively inhibits the proliferation of BRCA-deficient cancer cells, including those obtained from leukemia patients and is identified as a major allosteric inhibitor of the RAD52 ssDNA binding domain.

Journal ArticleDOI
TL;DR: This work constitutes the first global experimental analysis of protein lipidation in Leishmania, and reveals the extent of NMT-related biology yet to be explored for this neglected human pathogen.

Journal ArticleDOI
TL;DR: 6-(cyclohexylmethoxy)-N-(4-(vinylsulfonyl)phenyl)-9H-purin-2-amine (NU6300), the first covalent CDK2 inhibitor to be described, illustrates the potential of vinyl sulfones for the design of more potent and selective compounds.

Journal ArticleDOI
TL;DR: The discovery, isolation, and structural elucidation of streptomonomicin (STM), an antibiotic lasso peptide from Streptomonospora alba, and the genome for its producing organism demonstrate that understudied microbes remain fruitful reservoirs for the rapid discovery of novel, bioactive natural products.