Chemistry & Biology
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- Sciencedirect from 1994, Rcgp, Gale, CSA, Ingenta, and Proquest
Design, Synthesis, and Biological Evaluation of an Allosteric Inhibitor of HSET that Targets Cancer Cells with Supernumerary Centrosomes.
We report the discovery of an allosteric inhibitor of HSET, CW069, which we designed using a methodology on an interface of chemistry and biology. Using this approach, we explored millions of compounds in silico and utilized convergent syntheses. Only compound CW069 showed marked activity against HS...
N-carbamoylation of 2,4-diaminobutyrate reroutes the outcome in padanamide biosynthesis.
We identify the padanamide biosynthetic gene cluster and carry out systematic gene inactivation studies. Our results show that padanamides are synthesized by highly dissociated hybrid nonribosomal peptide synthetase/polyketide synthase machinery. We further demonstrate that carbamoyltransferase gene...
Unconventional origin and hybrid system for construction of pyrrolopyrrole moiety in kosinostatin biosynthesis.
Kosinostatin (KST), an antitumor antibiotic, features a pyrrolopyrrole moiety spirally jointed to a five-membered ring of an anthraquinone framework glycosylated with a γ-branched octose. By a combination of in silico analysis, genetic characterization, biochemical assay, and precursor feeding exper...
Fluorescence Imaging of Single-Copy DNA Sequences within the Human Genome Using PNA-Directed Padlock Probe Assembly.
We present an approach for fluorescent in situ detection of short, single-copy sequences within genomic DNA in human cells. The single-copy sensitivity and single-base specificity of our method is achieved due to the combination of three components. First, a peptide nucleic acid (PNA) probe locally...
Parasites R us: coronado biosciences recruits parasitic worms to treat autoimmune disease.
A selective inhibitor of heme biosynthesis in endosymbiotic bacteria elicits antifilarial activity in vitro.
We identified a benzimidazole compound, wALADin1, that selectively targets the δ-aminolevulinic acid dehydratase (ALAD) of Wolbachia (wALAD) and exhibits macrofilaricidal effects on Wolbachia-containing filarial worms in vitro. wALADin1 is a mixed competitive/noncompetitive inhibitor that interferes...
Catalytic site conformations in human PNP by 19F-NMR and crystallography.
We replaced catalytic site groups His257 or His64 with 6-fluoro-tryptophan (6FW) as site-specific NMR probes. Conformational adjustments in the 6FW-His257-helical and His64-6FW-loop regions were characterized in PNP phosphate-bound enzyme and in complexes with catalytic site ligands, including trans...
Decoding and recoding the ribosomal Peptide universe.
Ribosomal peptide natural products (RiPPs) offer a new frontier for discovering and engineering bioactive small molecules. In this issue of Chemistry & Biology, Young and colleagues overcome hurdles that have slowed the development of RiPPs, leading to in vivo synthesis of new thiopeptide antibiotic...
Molecular basis of in vivo biofilm formation by bacterial pathogens.
We lack information as to whether the biofilm formation mechanisms identified in vitro have relevance for biofilm-associated infection. Here, we discuss the molecular basis of biofilm formation. Staphylococci and Pseudomonas aeruginosa are used to illustrate key points because their biofilm developm...
Indirubin derivatives modulate TGFβ/BMP signaling at different levels and trigger ubiquitin-mediated depletion of nonactivated R-Smads.
We screened indirubin derivatives, known kinase inhibitors, and observed strong interference with BMP signaling. We found that indirubin derivative E738 inhibited both TGFβ and BMP pathways through ubiquitin-proteasome-mediated depletion of total R-Smad pools, although phospho-R-Smad levels were ini...