Asborin , the carbaborane analogue of aspirin, was obtained by a high‐yield synthetic procedure and proved to be an active cyclooxygenase (COX) inhibitor (H: white, B: beige, C: gray, O: blue).
Reversible mitochondrial shuttle : A novel concept in mitochondrial pharmacology allows the transport of bioactive compounds into the mitochondrial compartment and their subsequent release. A lipoic acid derivative containing a cleavable (“reversible”) triphenylphosphonium tag is endogenously cleaved by the mitochondrial aldehyde dehydrogenase (ALDH‐2) after mitochondrial accumulation.
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.
A protein TRAP : The in vivo photocrosslinking of TRAP after its intracellular targeting to a binding sequence on the bait protein stabilizes protein interactions. Because the crosslinker is releasable, simple mass spectrometry can be used to identify the protein binding sites after purification.
Fluorescent synthetic 7‐nitrobenzo‐2‐oxa‐1,3‐diazole (NBD) conjugates of cholic acid were prepared and characterized. Their photophysical properties make them suitable for monitoring uptake in freshly isolated rat hepatocytes using flow cytometry. This technique makes it possible to screen drug candidates for cholestatic (and thus hepatotoxic) liability.
Matrix evolutions : We have biochemically characterized the nacre matrix of the cephalopod Nautilus macromphalus, in part by a proteomic approach applied to the acetic acid‐soluble and ‐insoluble shell matrices, as well as to spots obtained after 2D gel electrophoresis. Strikingly, most of the obtained partial sequences are entirely new, whereas a few correspond only partly with bivalvian nacre proteins. Our findings shed new light on the macroevolution of nacre matrix proteins.
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.
H 3 R inverse agonists based on an aminopropoxy‐phenyloxazoline framework constitute highly valuable druglike lead compounds that display efficacy in a mouse model of recognition memory.
CypScore predicts the reactivity of competing positions in the same and different molecules to a variety of cytochrome P450 metabolic reactions on a single reactivity scale.
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 Great White Plague : Mycobacterium tuberculosis, the bacteria causing tuberculosis, is a continuing threat to global health through the emergence of resistant strains and the lack of novel therapeutic agents. Recently reported results on this important work are highlighted.
Light up galectin: Photoprobes based on thiodigalactoside were prepared for galectin‐3, a lectin linked to cancer. The probes contained either benzophenone or acetophenone moieties as the photolabel for covalent attachment to the protein. One particular probe labeled galectin‐3 selectively, even in the presence of cell lysate.
Azaspiracid antibodies : Immunization of azaspiracid immunoconjugates has elicited monoclonal antibodies with distinct epitopes on the marine toxin; this will open the way toward azaspiracid diagnostics and the detection of contaminated shellfish before they can enter the food supply.
Microbial fingerprints : We screened bacterial lipopolysaccharides (LPS) on random sequence peptide microarrays (see scheme); the results revealed distinct binding patterns for different bacteria. Most of the LPS binding sequences, which resemble natural antimicrobial peptides showed growth inhibition activity. This technology paves the way for systematic investigation of disease‐associated changes in poorly defined complex glycobiomolecules.
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.
Antifolate labels : Molecules that bind specifically and with high affinity to proteins can be developed into powerful tools for chemical biology. The interaction between substituted 5‐benzyl pyrimidines and dihydrofolate reductase can be exploited for chemically labeling fusion proteins in mammalian cells.
We present a method for fragment/scaffold substitution based on protein–ligand interactions. This concept goes beyond bioisosteric replacement, which only uses the structure of the fragment to replace as query. The methodology is validated with more than 10 biological targets relevant for drug discovery.
Remote control of cells : A polypeptide has been made that stimulates proliferation and migration of cells upon photochemical activation. This light‐activated polypeptide enables spatially defined control of cell populations at the scale of tissue organization; this is accomplished without physically contacting the cells or modifying their substrate.
The synthesis of 2′,2′‐difluoro KRN7000 is described. In vivo evaluation demonstrates that this fluorinated glycolipid induces CD1d‐dependent TCR activation of NKT cells, with a bias towards Th2 cytokine production.
Subtle change : Spatiotemporal modulation of individual protein subdomains with light as the trigger signal becomes possible by using bivalent aptamers and introducing photolabile “caging groups” to switch individual aptamer modules ON or OFF differentially. To the best of our knowledge, this is the first study to show that it is possible to modulate individual domain activity in aptamers, and thus also domain activity in proteins, with light.
