Two series of dimeric ligands for a G‐protein‐coupled receptor were prepared that differ by the interconnecting spacer system. Biological evaluation revealed that both dimeric series exhibit unique biological properties relative to their monomeric counterparts.
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.
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.
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.
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.
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.
Synthetic cancer vaccines : A number of fully synthetic vaccine candidates have been designed, chemically synthesized, and immunologically evaluated to establish a strategy to overcome the poor immunogenicity of tumor‐associated carbohydrates and glycopeptides and to determine the importance of Toll‐like receptor (TLR) engagement for antigenic responses against these compounds.
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.
Molecules that inhibit store‐operated calcium entry (SOCE) are potentially useful immunomodulating agents. The identification of proteins involved in this pathway may further enable the identification of selective inhibitors. Herein we document some examples of the small‐molecule inhibitors of SOCE that have been reported to date. We also describe methods that were used to characterize the mechanism of action of these inhibitors.
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.
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.
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.
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.
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.
Cells in the balance : Programmed cell death is an important and stringently controlled process. Aberrancies in its control mechanisms can lead to disease; overactive apoptosis can cause neurodegenerative disorders, whereas deficient apoptotic activity can lead to cancer. Therefore, controlling apoptotic pathways with peptides is showing increasing promise as a strategy in drug development.
A QSAR model for the prediction of CNS activity was developed and validated based on data from an in‐house database of “drug‐like” compounds. The model has demonstrated its applicability for novel chemical structures and its usefulness for the design of CNS‐focused compound libraries.
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.
Insider information : Selective labeling of endogenous proteins within cells has been an elusive goal. Here carrier protein labeling has been optimized for visualization, isolation, and protein sequencing.
A series of DNA methyltransferase 1 (DNMT1) inhibitors were modeled by docking and molecular dynamics studies to rationalize their activity. Our findings will be valuable in guiding research efforts toward the rational design and virtual screening of novel DNMT inhibitors.
Covalent bonds not required : We describe a novel approach in which the concepts of fragment‐based ligand discovery are combined with chemical array techniques to yield bivalent inhibitors. A pair of fragments is mixed and covalently attached to a glass slide by photolinking immobilization. The method does not require the compounds to have specific functional groups, and tedious steps for protein purification are avoided. Thus, the on‐chip fragment‐based approach is relatively simple and efficient for obtaining high‐affinity ligands.
