Murine astrovirus (MuAstV) infection in mouse facilities in Brazil: First South American report.

This study aimed to investigate the presence of murine astrovirus (MuAstV) in Brazil. Fecal samples from mice belonging to four Brazilian animal facilities were collected and tested for MuAstV using real-time polymerase chain reaction. Of the 162 samples tested, 38 (23.

Fragment-Based Interrogation of the 14-3-3/TAZ Protein-Protein Interaction.

The identification of chemical starting points for the development of molecular glues is challenging. Here, we employed fragment screening and identified an allosteric stabilizer of the complex between 14-3-3 and a TAZ-derived peptide. The fragment binds preferentially to the 14-3-3/TAZ peptide complex and shows moderate stabilization in differential scanning fluorimetry and microscale thermophoresis.

Protection of pancreatic islets from oxidative cell death by a peripherally-active morphinan with increased drug safety.

Objective: Dextromethorphan (DXM) is a commonly used antitussive medication with positive effects in people with type 2 diabetes mellitus, since it increases glucose tolerance and protects pancreatic islets from cell death. However, its use as an antidiabetic medication is limited due to its central nervous side effects and potential use as a recreational drug. Therefore, we recently modified DXM chemically to reduce its blood-brain barrier (BBB) penetration and central side effects.

Cellular model system to dissect the isoform-selectivity of Akt inhibitors.

The protein kinase Akt plays a pivotal role in cellular processes. However, its isoforms' distinct functions have not been resolved to date, mainly due to the lack of suitable biochemical and cellular tools. Against this background, we present the development of an isoform-dependent Ba/F3 model system to translate biochemical results on isoform specificity to the cellular level.

An Exploration of Chemical Properties Required for Cooperative Stabilization of the 14-3-3 Interaction with NF-κB-Utilizing a Reversible Covalent Tethering Approach.

Protein-protein modulation has emerged as a proven approach to drug discovery. While significant progress has been gained in developing protein-protein interaction (PPI) inhibitors, the orthogonal approach of PPI stabilization lacks established methodologies for drug design. Here, we report the systematic ″bottom-up″ development of a reversible covalent PPI stabilizer.

Reversible Covalent Imine-Tethering for Selective Stabilization of 14-3-3 Hub Protein Interactions.

The stabilization of protein complexes has emerged as a promising modality, expanding the number of entry points for novel therapeutic intervention. Targeting proteins that mediate protein-protein interactions (PPIs), such as hub proteins, is equally challenging and rewarding as they offer an intervention platform for a variety of diseases, due to their large interactome. 14-3-3 hub proteins bind phosphorylated motifs of their interaction partners in a conserved binding channel.

Fragment-Based Stabilizers of Protein-Protein Interactions through Imine-Based Tethering.

Small-molecule stabilization of protein-protein interactions (PPIs) is a promising concept in drug discovery, however the question how to identify or design chemical starting points in a "bottom-up" approach is largely unanswered. We report a novel concept for identifying initial chemical matter for PPI stabilization based on imine-forming fragments. The imine bond offers a covalent anchor for site-directed fragment targeting, whereas its transient nature enables efficient analysis of structure-activity relationships.

Set-up and screening of a fragment library targeting the 14-3-3 protein interface.

Protein-protein interactions (PPIs) are at the core of regulation mechanisms in biological systems and consequently became an attractive target for therapeutic intervention. PPIs involving the adapter protein 14-3-3 are representative examples given the broad range of partner proteins forming a complex with one of its seven human isoforms. Given the challenges represented by the nature of these interactions, fragment-based approaches offer a valid alternative for the development of PPI modulators.

Efficient synthesis of the structural core of tetracyclines by a palladium-catalyzed domino Tsuji-Trost-Heck-Mizoroki reaction.

The Pd-catalyzed domino Tsuji-Trost-Heck-Mizoroki reactions of compounds 18, 27, and 34, respectively, each containing an allyl acetate and a halogen aryl moiety, lead to the formation of hexahydronaphthacenes 2 and 3 and octahydroanthracene 4 in 62-81 % yield. The octahydroanthracene and hexahydronaphthacene motifs are found in many natural products, for example, the tetracycline antibiotics.

Characterisation of fungal lanostane-type triterpene acids by electrospray ionisation mass spectrometry.

Lanostane-triterpene acids obtained from the culture of the fungus Coriolellus malicola were studied by electrospray mass spectrometry in the negative ion mode using quadrupole time-of-flight and quadrupole ion trap analysers. Despite the differences observed in the mass spectra recorded with these instruments, a set of fragment ions was found to be characteristic of the family, depending on the Delta(7,9(11)) or Delta(8) skeleton and the particular functional group at C-3.

Biaryl synthesis via Pd-catalyzed decarboxylative coupling of aromatic carboxylates with aryl halides.

A new strategy for the regiospecific construction of unsymmetrical biaryls is presented, in which easily available salts of carboxylic acids are decarboxylated in situ to give arylmetal species that serve as the nucleophilic component in a catalytic cross-coupling reaction with aryl halides. The catalyst system consists of a copper phenanthroline complex that mediates the extrusion of CO2 from aromatic carboxylates to generate arylcopper species, and a palladium complex that catalyzes the cross-coupling of these intermediates with aryl halides. This bimetallic system allows the direct coupling of various aryl, heteroaryl, or vinyl carboxylic acids with aryl or heteroaryl iodides, bromides, or chlorides at 160 degrees C in the presence of a mild base such as potassium carbonate.

Synthesis of biaryls via catalytic decarboxylative coupling.

We present a safe and convenient cross-coupling strategy for the large-scale synthesis of biaryls, commercially important structures often found in biologically active molecules. In contrast to traditional cross-couplings, which require the prior preparation of organometallic reagents, we use a copper catalyst to generate the carbon nucleophiles in situ, via decarboxylation of easily accessible arylcarboxylic acid salts. The scope and potential economic impact of the reaction are demonstrated by the synthesis of 26 biaryls, one of which is an intermediate in the large-scale production of the agricultural fungicide Boscalid.

Is the ring conformation the most critical parameter in lipase-catalysed acylation of cycloalkanols?

CAL-B catalysed the resolution of several five and six-membered cyclic beta-hydroxy esters efficiently with the exception of the cis-cyclohexanol (+/-)-4. When employing molecular modelling techniques the conformation turned out to be the most important determinant for their reactivity towards O-acetylation. In all cases, the R enantiomers reacted faster than the S enantiomers since the reactive intermediates of the former can adopt more favourable ring conformations and thus experience less steric hindrance in the active site.

Synthesis and enzymatic kinetic resolution of alpha,alpha-disubstituted cyclic hydroxy nitriles.

Herein, we describe the diastereoselective synthesis of five- and six-membered alpha,alpha-disubstituted cyclic beta-hydroxy nitriles and their resolution via enzymatic transesterification. By this method, all possible stereoisomers were obtained in enantiopure form and high yield.

5H-furan-2-ones from fungal cultures of Aporpium caryae.

Four furanones 1-4 with an unusual skeleton containing an acetylene unit, named aporpinones, were isolated from the culture of the basidiomycete Aporpium caryae and their structures were elucidated by spectroscopic methods. Compounds 3 and 4 showed weak to moderate antibacterial activity against Bacillus subtilis, Staphylococcus aureus and Escherichia coli.