With a Hunsdiecker–Barton iododecarboxylation strategy, we converted the carboxylate group of the oseltamivir precursor into exemplary phosphonate monoesters. In all cases, Ki values towards influenza virus sialidase remained in the sub‐nanomolar range. We have thus made valuable structural space available for the design of novel oseltamivir‐based tools for influenza virus research.
Roll with it : The quantitative analysis of specific miRNAs from biological samples is very likely to revolutionize diagnostics of human disease. A novel method for miRNA analysis employing rolling‐circle amplification (RCA) can homogeneously detect miRNA, even at concentrations as low as 10 fM . The use of T4 RNA ligase 2 (T4 RnL2) at elevated temperatures enables very good discrimination of miRNAs differing by a single nucleotide.
Enzyme‐mediated synthesis of phosphatidylinositol : Engineered phospholipase D enzymes enable the synthesis of phosphatidylinositol by transphosphatidylation. The 1‐ or 3‐hydroxy group of myo‐inositol is selectively reacted.
Molecular requirements and determinants for efficient binding to CCR5 were interpreted by computational techniques based on comparative receptor structure modeling, advanced 3D‐QSAR, docking, and shape‐based virtual screening of commercially available entry blockers. Results of this study may be valuable for predicting new HIV entry‐blocking leads.
New and improved : The incorporation of a 6‐chlorotryptophan (6‐Cl‐Trp) into a β‐peptide (M)‐314 helix leads to a high‐affinity hDM2 inhibitor, as demonstrated by fluorescence fluctuation analysis at single molecule resolution. When conjugated to penetratin, the newly derived hDM2 binder specifically inhibits tumour cell growth in vitro.
Prodigiosin : Amido‐functionalised prodigiosin‐derived compounds were synthesised via a robust and efficient synthetic route. These compounds were then evaluated against 60 human cell lines consisting of nine diverse tumour cell types and their anticancer activities were assessed.
Target TAR by NMR : Tripeptides containing arginines as terminal residues and non‐natural amino acids as central residues are good leads for drug design to target the HIV trans‐activation response element (TAR). The structural characterization of the RNA–ligand complex by NMR spectroscopy reveals two specific binding sites that are located at bulge residue U23 and around the pyrimidine‐stretch U40‐C41‐U42 directly adjacent to the bulge.
Binding of the mGlu2/3 antagonist HYDIA in the closed conformation model of mGlu2 causes repulsive interactions with Y216 in lobe II of the binding pocket, preventing closure of the VFT.
The spatiotemporal expression of cannabinoid receptors and endocannabinoid‐metabolising enzymes during brain development guides major developmental processes including neurogenesis, cell differentiation, cell migration, neuronal specification and synaptogenesis.
The electronic and physical structure of the active centre of nitrogenase is described from an inorganic point of view, the central main‐group element is determined and its role within the cluster is explained.
Tetrahedral DNA hybrids with tetrakis(p‐hydroxyphenyl)methane cores hybridize in a sequence‐specific fashion at much higher temperatures than isolated linear duplexes. Dinucleotide DNA arms suffice to induce the formation of a solid at room temperature; this demonstrates the strength of multivalent binding. The graphic shows a view of a modeled assembly.
Form defines function : The effects of β‐hairpin structure on the binding affinity and selectivity for ssDNA versus dsDNA were investigated; this provided insights into the factors that contribute to the selective recognition of both ss‐ and dsDNA and suggested new approaches for designing biomimetic receptors. Binding studies showed that 1) folding is crucial for binding to both ss‐ and dsDNA, and 2) chirality affects binding for duplex but not for ssDNA.
Making the microbes work for us : An acyl‐carrier‐protein‐centered strategy that involves two distinct acyl‐transfer steps for generation and regiospecific attachment of the 5‐chloro‐6‐methyl‐O‐methylsalicyl group onto the C3′ position of D ‐olivose was elucidated in the biosynthetic pathway of chlorothricin. Identification of the mutant of the acyltransferase‐associated intermediate validated the critical role of the highly conserved Cys residue, which channels the acyl transfer by using its thiolate side chain as a nucleophile in a two‐step process.
A novel series of diarylpyrimidine analogues (DAPYs) featuring a naphthyl moiety at the C4 position were designed, with all compounds exhibiting strong activity against wild‐type HIV‐1.
2‐Benzamidobenzoic acids seem to stabilize PTPN22 phosphatase in its inactive 'open' conformation with the WPD loop locked in a distal position. In silico screening using both 3D structures in open and closed conformations yielded potent inhibitors of this potential drug target for autoimmunity that specifically dock into its open form. Tryptophan fluorescence measurements support the proposed binding mode.
SDS‐concentration‐dependent α‐synuclein structure : Upon interaction with SDS, αSyn folds into a structure with two antiparallel α‐helices. We show from single‐molecule FRET that αSynn adopts this conformation in an all‐or‐none fashion below the SDS critical micelle concentration. Population of the folded species is directly coupled to an increase in α‐helix content; this suggests that the entire N terminus is involved in the transaction.
Virtual screening discovered two prospective hits as potential leads for aldose reductase inhibition. Based on their crystal structures with the enzyme, a systematic optimization has been performed to reveal a first structure–activity relationship. A central thiophen moiety and a terminal nitro group exhibit the best binding properties.
The big screen : We have devised a high‐throughput screening method for organic peroxide‐dependent P450 reactivity by taking advantage of a previously undescribed activity of catalase, which was used as reporter enzyme. This two‐step assay, followed by liquid chromatography/mass spectrometry analyses, allowed the facile identification of several new substrates for bacterial P450 enzymes.
Zinc‐dependent metalloproteinases such as matrix metalloproteinases (MMPs) and A disintegrin and metalloproteinases (ADAMs) are potential therapeutic targets in many diseases. To better understand their complex role in health and disease, new methodology for activity determination is under development. This concept gives an overview of the available methods for activity‐based proteomic research on these enzymes.
Powerful pyrene probes : Two kinds of pyrene‐labeled oligonucleotides (HNA‐ and RNA‐skeleton probes) were explored. The enhanced fluorescence intensity in the monomer region and the disappearance of aggregate/excimer emission in duplexes has been successfully used to detect the hybridization of oligonucleotides.
