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.
An inference network model for molecular similarity searching: The similarity search problem is modeled using inference or evidential reasoning under uncertainty. The inference network model treats similarity searching as an evidential reasoning process in which multiple sources of evidence about compounds and reference structures are combined to estimate resemblance probabilities.
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.
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.
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.
Unexpected inhibition : 2‐ and 4‐mono‐ and difluoromethyl estrone sulfate derivatives are suicide inhibitors of steroid sulfatase (STS). Kinetic studies suggest that inhibition by the monofluoro derivatives is a result of a quinone methide intermediate that reacts with active‐site nucleophiles, whereas the main inhibition pathway of the 4‐difluoromethyl derivative is a result of decomposition of the initial quinone methide to an aldehyde that acts as potent, almost irreversible inhibitor.
Combating glycolipid storage disorders : LABNAc was prepared in an efficient 11‐step procedure from D ‐lyxonolactone. The enantiomer DABNAc was also prepared from L ‐lyxonolactone. Preliminary cellular studies indicate that these compounds may find utility as chemical chaperones for the treatment of Tay‐Sachs and Sandhoff diseases.
Access to enantiopure β‐amino acids : β‐Aminopeptidases are hydrolases that possess the unique ability to cleave N‐terminal β‐amino acids from peptides and amides. Hydrolysis of racemic β‐amino acid amides catalyzed by these enzymes displays enantioselectivity with strong preference for substrates with the L ‐configuration, and gives access to various aliphatic β‐amino acids of high enantiopurity.
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.
Anchors aweigh! The synthesis of tryptophan–amphotericin B conjugates (see figure) is described. The membrane‐anchoring effect of tryptophane was thus combined with the pore‐formation effect of amphotericin B leading to high channel activity in sterol‐free liposomes.
The 2‐aryloxazole and 2‐arylthiazole scaffolds were used for generating compounds that we characterized for their inhibitory activity toward ATP binding cassette transporters involved in multi‐drug resistance, such as BCRP and MRP1, by using tumor cell lines overexpressing each transporter. These SAR studies are a significant step toward improving the inhibitory potency against P‐glycoprotein, BCRP, and MRP1.
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.
Acetylcholinesterase inhibitors : We extended the AChE inhibitors SAR study to newly synthesized compounds based on the lead compound xantostigmine. Docking and molecular dynamics simulations were carried out to both define a new computational protocol, and to acquire a better understanding of the SAR data. These computations prompted us to evaluate two of the synthesized compounds as inhibitors of AChE‐induced Aβ aggregation.
Glycan binding : We monitored the binding of synthetic glycans to influenza hemagglutinin by using ELISA and surface plasmon resonance, thereby demonstrating that the glycan's presentation influences binding dramatically. Also, the binding observed in static systems was very different from that in dynamic fluid systems. These studies suggest that binding specificities are dependent on glycan structure, valency, presentation, and assay conditions.
Playing polo : Small‐molecule inhibitors of polo‐like kinase 1 are mostly ATP‐competitive, and thus face enormous specificity hurdles. This communication explores the concept of inhibiting Plk1 with a small‐molecule inhibitor of the protein–protein interactions required for Plk1 function.
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.
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.
Illuminating glucosidases : The shown photoaffinity probe for endoplasmic reticulum (ER) α‐glucosidases was found to be a highly potent inhibitor of α‐glucosidase I in vitro and equally effective at inhibiting cellular ER glucosidases, as determined by a free oligosaccharide (FOS) analysis.
Designer label : A newly developed polarity‐sensitive fluorescent probe (DBHA) was combined with a tyrosine‐specific labelling method that uses transition metal catalysis, and was successfully used in local structural analysis of the Tyr108 domain in Cu/Zn superoxide dismutase (SOD; see scheme). The strategy presented here provides a new approach for studying the local polarity and conformation changes of this tyrosine domain in SOD under acid or heat denaturation conditions.
Unsaturated Mannich bases with potent antitrypanosomal action against multidrug‐resistant strains of T. brucei brucei were identified. Their observed activities correlated well with their high Michael acceptor properties but not with their affinities to the P2 purine transporter.
