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.
Histamine mediates its various functions through four histamine receptor subtypes. The H3 subtype is mainly found in the central nervous system, where it modulates the release of histamine and other neurotransmitters, whereas the H4 subtype plays a crucial role in inflammatory and immunological processes. Herein, the synthesis and characterization of a conveniently accessible tritiated radioligand is reported that proved to be a versatile pharmacological probe.
On and off in a flash : We describe a novel, ultrafast, reversible, interstrand RNA photocrosslinking reaction via 3‐cyanovinylcarbazole nucleoside. The interstrand RNA‐photocrosslinking reaction showed a high degree of sequence specificity and can be used in the selection of a target RNA sequence.
Plaque visualisation : We identified three different D ‐enantiomeric peptides that bind to Alzheimer's amyloid β (Aβ1‐42). As there is currently no definitive pre‐mortem diagnosis for Alzheimer's disease, we investigated the peptides' suitability as molecular probes for in vivo imaging in transgenic mouse models.
Artificial synapses for femtomolar detection : Amperometry at platinized carbon fibre electrodes has been used to unravel the complexity of β‐lapachone's effects on cellular oxidative stress. α‐Lapachone, the pharmacologically inactive para‐quinone isomer, did not display such characteristics, but over longer incubation periods both quinones induced apoptosis. The observed effects were interpreted in terms of two mechanisms involving opposite reactivities of quinones in living cells.
Monooxygenase mutants : A minimal and highly enriched CYP102A1 mutant library was constructed by combining five hydrophobic amino acids in two positions. The library was screened with four different terpene substrates. Eleven variants demonstrated either a strong shift or improved regio‐ or stereoselectivity during oxidation of at least one substrate as compared to CYP102A1 wild type.
Peptides that inhibit cyclin‐dependent kinase 2 by blocking the macromolecular substrate recruitment site of cyclin A were simplified, for example, by replacement of dipeptide units with β‐amino acids. The smallest inhibitor retaining activity was a tripeptide, whose binding mode was confirmed by X‐ray crystallography. This result suggests that nonpeptidic cyclin groove inhibitors may be feasible therapeutic agents.
Novel and potent inhibitors of Plasmodium falciparum plasmepsin II were identified by post‐processing the results of a docking screening with BEAR, a recently reported procedure for the refinement and rescoring of docked ligands in virtual screening. FRET substrate degradation assays performed on the 30 most promising compounds resulted in 26 inhibitors with IC50 values ranging from 4.3 nM to 1.8 μM .
Illuminating an ER enzyme : We report on the design and synthesis of a fluorogenic chemical sensor ( 1 ) to measure sphingosine‐1‐phosphate lyase activity in high‐throughput screening formats, as well as its validation using lyase knockout (Sgpl1?/?) cells.
A fluorescent biosensor is described for 2Fe2S clusters that is composed of green fluorescent protein (GFP) fused to glutaredoxin 2 (Grx2), as illustrated here. 2Fe2S detection is based on the reduction of GFP fluorescence upon the 2Fe2S‐induced dimerization of GFP‐Grx2. This assay is sufficiently sensitive to detect submicromolar changes in 2Fe2S levels, thus making it suitable for high‐throughput measurements of metallocluster degradation and synthesis reactions.
Coculture control : We report a combined photochemical and electroactive self‐assembled monolayer (SAM)‐based substrate strategy to generate a coculture platform with spatial and temporal control of cell–cell interactions. These dynamic substrates can present a variety of ligands on the surface for biospecific interactions between the ligands and cell surface receptors. Photopatterning enables the ligands to be immobilized in patterns and even gradients.
Flexibility required : We designed intramolecular bipartite tetracysteine sites in loops of p53 and the β‐sheets of EmGFP. We found that ReAsH binding preferentially favors tetracysteine sites with flexible geometries such as loops; flexibility was assessed by comparing Cα B‐factor values. This information is important for directing successful bipartite tetracysteine site designs.
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.
Interactions between C34 and N36 : Synthetic peptides with D ‐amino acid substitutions that mimic the human immunodeficiency virus (HIV) gp41 HR2 region may lead to new peptidic anti‐HIV‐1 drugs that retain potent antiviral activity while being more resistant to proteolytic degradation.
Long‐lasting sweet proteins : The chemoenzymatic synthesis of a triazole (T)‐linked glycosylated C34 fragment from HIV‐1 gp41 is described. The glycopeptide shows high solubility, excellent fusion inhibition, and as shown in the graph, promising protease resistance.
Broad‐spectrum antibiotics with heterocyclic side chains strongly inhibit peroxidase‐catalyzed iodination in the presence of metallo‐β‐lactamase. This suggests that antibiotic resistance due to hydrolysis of the β‐lactam ring in antibiotics would have negative effects on thyroid activity.
Out of the green! Precursor‐directed biosynthesis allowed for the production of new nostocarboline derivatives that display phytotoxic and algicidal properties—in a phototrophic organism. The mechanism of action includes downregulation of photosynthesis, as demonstrated by chlorophyll‐a fluorescence imaging.
A panel of new potential Ras ligands was generated by decorating a tricyclic levoglucosenone‐derived scaffold with aromatic moieties. Some members of the panel show in vitro inhibitory activity toward the nucleotide exchange process on Ras and are toxic to some human cancer cell lines.
Last at last : The terminal step of the gilvocarcin V (GV) biosynthetic pathway is an unusual lactone formation. Here we show that the enzyme, GilR, dehydrogenates the hemiacetal moiety of pregilvocarcin V to the lactone found in GV by using covalently bound FAD.
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.
