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.
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.
Come together right now with L ‐DOPA : Chemical cross‐linking is widely used to study protein–protein interactions. However, many cross‐linking agents suffer from low reactivity or selectivity. An efficient and selective reaction of site‐specific protein cross‐linking was achieved using genetically incorporated 3,4‐dihydroxy‐L ‐phenylalanine.
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.
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.
Oxidation of a specific cysteine residue to Cα‐formylglycine is a novel post‐translational modification that is directed by a short recognition motif commonly found in pro‐ and eukaryotic sulfatases. As recently shown by C. Bertozzi and co‐workers, this system can be employed in protein engineering to equip proteins with genetically encoded aldehyde tags for site‐specific labeling, conjugation and immobilization.
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.
A mechanism for triflusal‐induced photoallergy involving complexation of 2‐hydroxy‐4‐trifluoromethylbenzoic acid with site I of human serum albumin and subsequent formation of a covalent adduct by photoreaction between a metabolite and a neighboring lysine residue is proposed. This is supported by the observed photobinding to poly‐L ‐lysine. Thereby, a photoantigen is generated, which is a likely trigger of the immune response.
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 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.
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.
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.
Combretastatin A‐4 derivatives : A series of combretastatin A‐4‐derived 1‐benzyl‐4,5,6‐trimethoxyindoles was designed and prepared as a novel class of potent antimitotic agents acting through the colchicine binding site on the microtubule.
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.
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.
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.
Transforming the neuroactive toxins of cone snails into small‐size compounds poses a challenge due to the presence of multiple disulfide bridges. Herein we describe our successful efforts in minimizing the size of μ‐conotoxin while retaining its biological activity.
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.
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.
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.
