- Profiling withanolide A for therapeutic targets in neurodegenerative diseases
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To identify new potential therapeutic targets for neurodegenerative diseases, we initiated activity-based protein profiling studies with withanolide A (WitA), a known neuritogenic constituent of Withania somnifera root with unknown mechanism of action. Molecular probes were designed and synthesized, and led to the discovery of the glucocorticoid receptor (GR) as potential target. Molecular modeling calculations using the VirtualToxLab predicted a weak binding affinity of WitA for GR. Neurite outgrowth experiments in human neuroblastoma SH-SY5Y cells further supported a glucocorticoid-dependent mechanism, finding that WitA was able to reverse the outgrowth inhibition mediated by dexamethasone (Dex). However, further GR binding and transactivation assays found no direct interference of WitA. Further molecular modeling analysis suggested that WitA, although forming several contacts with residues in the GR binding pocket, is lacking key stabilizing interactions as observed for Dex. Taken together, the data suggest that WitA-dependent induction of neurite outgrowth is not through a direct effect on GR, but might be mediated through a closely related pathway. Further experiments should evaluate a possible role of GR modulators and/or related signaling pathways such as ERK, Akt, NF-κB, TRα, or Hsp90 as potential targets in the WitA-mediated neuromodulatory effects.
- Crane, Erika A.,Heydenreuter, Wolfgang,Beck, Katharina R.,Strajhar, Petra,Vomacka, Jan,Smiesko, Martin,Mons, Elma,Barth, Lydia,Neuburger, Markus,Vedani, Angelo,Odermatt, Alex,Sieber, Stephan A.,Gademann, Karl
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- Multivalent display and receptor-mediated endocytosis of transferrin on virus-like particles
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The structurally regular and stable self-assembled capsids derived from viruses can be used as scaffolds for the display of multiple copies of cell- and tissue-targeting molecules and therapeutic agents in a convenient and well-defined manner. The human iron-transfer protein transferrin, a high affinity ligand for receptors upregulated in a variety of cancers, has been arrayed on the exterior surface of the protein capsid of bacteriophage Qβ. Selective oxidation of the sialic acid residues on the glycan chains of transferrin was followed by introduction of a terminal alkyne functionality through an oxime linkage. Attachment of the protein to azide-functionalized Qβ capsid particles in an orientation allowing access to the receptor binding site was accomplished by the CuI-catalyzed azide-alkyne cycloaddition (CuAAC) click reaction. Transferrin conjugation to Qβ particles allowed specific recognition by transferrin receptors and cellular internalization through clathrin-mediated endocytosis, as determined by fluorescence microscopy on cells expressing GFP-labeled clathrin light chains. By testing Qβ particles bearing different numbers of transferrin molecules, it was demonstrated that cellular uptake was proportional to ligand density, but that internalization was inhibited by equivalent concentrations of free transferrin. These results suggest that cell targeting with transferrin can be improved by local concentration (avidity) effects.
- Banerjee, Deboshri,Liu, Allen P.,Voss, Neil R.,Schmid, Sandra L.,Finn
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- A minimally-masked inactive prodrug of panobinostat that is bioorthogonally activated by gold chemistry
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The recent incorporation of Au chemistry in the bioorthogonal toolbox has opened up new opportunities to deliver biologically independent reactions in living environments. Herein we report that the O-propargylation of the hydroxamate group of the potent HDAC inhibitor panobinostat leads to a vast reduction of its anticancer properties (>500-fold). We also show that this novel prodrug is converted back into panobinostat in the presence of Au catalysts in vitro and in cell culture.
- Rubio-Ruiz, Belén,Pérez-López, Ana M.,Sebastián, Víctor,Unciti-Broceta, Asier
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- With biological activity mixed oxygen benzene oxygen N- the oxygen radical is thick carboxylic acid amide compound and its preparation method
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The present invention discloses a N-oxyl fused heterocycle oxy phenoxy carboxylic acid amide compound having biological activity, and a preparation method thereof, wherein the compound is represented by a formula (I), A is selected from the following groups, R is C3-C6 alkenyl, C3-C6 alkynyl, C3-C6 halogenated alkenyl, C3-C6 halogenated alkynyl, C3-C6 cycloalkyl methyl and C3-C6 halogenated cycloalkyl alkyl methyl, R1 is H, C1-C3 alkyl, and C1-C3 halogenated alkyl, and R2 is H, halogen, C1-C3 alkyl, and C1-C3 halogenated alkyl. The compound represented by the formula (I) has broad-spectrum biological activity of weed removing or insect killing and bacterial killing, wherein some compounds have high weed removing activity and can achieve a good prevention and control effect at a use amount of 3.75-75 g effective component/hectare.
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Paragraph 0071; 0072; 0074
(2016/10/08)
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- One-pot: N -glycosylation remodeling of IgG with non-natural sialylglycopeptides enables glycosite-specific and dual-payload antibody-drug conjugates
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Chemoenzymatic transglycosylation catalyzed by endo-S mutants is a powerful tool for in vitro glycoengineering of therapeutic antibodies. In this paper, we report a one-pot chemoenzymatic synthesis of glycoengineered Herceptin using an egg-yolk sialylglycopeptide (SGP) substrate. Combining this one-pot strategy with novel non-natural SGP derivatives carrying azido or alkyne tags, glycosite-specific conjugation was enabled for the development of new antibody-drug conjugates (ADCs). The site-specific ADCs and semi-site-specific dual-drug ADCs were successfully achieved and characterized with SDS-PAGE, intact antibody or ADC mass spectrometry analysis, and PNGase-F digestion analysis. Cancer cell cytotoxicity assay revealed that small-molecule drug release of these ADCs relied on the cleavable Val-Cit linker fragment embedded in the structure. These results represent a new approach for glycosite-specific and dual-drug ADC design and rapid synthesis, and also provide the structural requirement for their biologic activities.
- Tang, Feng,Yang, Yang,Tang, Yubo,Tang, Shuai,Yang, Liyun,Sun, Bingyang,Jiang, Bofeng,Dong, Jinhua,Liu, Hong,Huang, Min,Geng, Mei-Yu,Huang, Wei
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supporting information
p. 9501 - 9518
(2016/10/22)
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- METHODS FOR POST-FABRICATION FUNCTIONALIZATION OF POLY(ESTER UREAS)
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Amino acid-based poly(ester urea)s (PEU) are emerging as a class of polymers that have shown promise in regenerative medicine applications. Embodiments of the invention relate to the synthesis of PEUs carrying pendent "clickable" groups on modified tyrosine amino acids. The pendent species include alkyne, azide, alkene, tyrosine-phenol, and ketone groups. PEUs with Mw exceeding 100k Da were obtained via interfacial polycondensation methods and the concentration of pendent groups was varied by copolymerization. The incorporation of derivatizable functionalities is demonstrated using 1H NMR and UV-Vis spectroscopy methods. Electrospinning was used to fabricate PEU nanofibers with a diameters ranging from 350 nm to 500 nm. The nanofiber matricies possess mechanical strengths suitable for tissue engineering (Young's modulus: 30045 MPa; tensile stress: 8.51.2 MPa). A series of bioactive peptides and fluorescent molecules were conjugated to the surface of the nanofibers following electrospinning using bio-orthogonal reactions in aqueous media.
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Paragraph 00235
(2015/04/15)
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- NOVEL VASCULAR LEAKAGEAGE INHIBITOR
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The present disclosure relates to a novel vascular leakage inhibitor. The novel vascular leakage inhibitor of the present invention inhibits the apoptosis of vascular endothelial cells, inhibits the formation of actin stress fibers induced by VEGF, and enhances the cortical actin ring structure, thereby inhibiting vascular leakage. Accordingly, the vascular leakage inhibitor of the present invention can prevent or treat various diseases caused by vascular leakage. Since the vascular leakage inhibitor of the present invention is synthesized from commercially available or easily synthesizable pregnenolones, it has remarkably superior feasibility of commercial synthesis.
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Paragraph 0093
(2015/01/07)
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- NOVEL ORALLY BIOAVAILABLE BREATHING CONTROL MODULATING COMPOUNDS, AND METHODS OF USING SAME
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The present invention includes compositions that are useful in the prevention and/or treatment of breathing control diseases or disorders in a subject in need thereof. The present invention also includes a method of preventing and/or treating a respiratory disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition of the invention. The present invention further includes a method of preventing destabilization or stabilizing breathing rhythm in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition of the invention.
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Page/Page column 204-205
(2014/06/11)
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- Glucal-conjugated sterols as novel vascular leakage blocker: Structure-activity relationship focusing on the C17-side chain
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A series of glucal-conjugated sterols as novel vascular leakage blocker were identified through design, synthesis and biologically evaluation. In addition, the structure-activity relationship (SAR) of the glucal-conjugated sterols focusing on the C17-side chain was also established. The sterol analogs linked with the rigid C17-side chain side chains exhibited potent cell survival activities. In particular, analog 21l, which possesses a cyclopentyl oxime moiety, was shown to have excellent pharmacological effects on retinal vascular leakage in a diabetic mouse model.
- Kim, Kyeojin,Maharjan, Sony,Lim, Changjin,Kim, Nam-Jung,Agrawal, Vijayendra,Han, Young Taek,Lee, Sujin,An, Hongchan,Yun, Hwayoung,Choi, Hyun-Jung,Kwon, Young-Guen,Suh, Young-Ger
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p. 184 - 194
(2014/03/21)
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- New indenoindolone compounds
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Compound of formula (I): wherein R represents hydrogen, optionally substituted alkyl or alkenyl, R1 to R8, which may be identical or different, each represents hydrogen, optionally substituted alkyl, hydroxy, acyloxy, optionally subs
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- PYRAZOLE DERIVATIVES
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The present invention relates to pyrazole derivatives of the formula (I), and herbicides containing them as active ingredients. According to the present invention, novel pyrazole derivatives and herbicides containing them as active ingredients which exhib
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