- Stapling of two PEGylated side chains increases the conformational stability of the WW domain via an entropic effect
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Hydrocarbon stapling and PEGylation are distinct strategies for enhancing the conformational stability and/or pharmacokinetic properties of peptide and protein drugs. Here we combine these approaches by incorporating asparagine-linked O-allyl PEG oligomers at two positions within the β-sheet protein WW, followed by stapling of the PEGs via olefin metathesis. The impact of stapling two sites that are close in primary sequence is small relative to the impact of PEGylation alone and depends strongly on PEG length. In contrast, stapling of two PEGs that are far apart in primary sequence but close in tertiary structure provides substantially more stabilization, derived mostly from an entropic effect. Comparison of PEGylation + stapling vs. alkylation + stapling at the same positions in WW reveals that both approaches provide similar overall levels of conformational stability.
- Xiao, Qiang,Bécar, Natalie A.,Brown, Nathaniel P.,Smith, Mason S.,Stern, Kimberlee L.,Draper, Steven R.E.,Thompson, Katherine P.,Price, Joshua L.
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- Helix versus coil polypeptide macromers: Gel networks with decoupled stiffness and permeability
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As a platform for investigating the individual effects of substrate stiffness, permeability, and ligand density on cellular behavior, we developed a set of hydrogels with stiffness tuned by polymer backbone rigidity, independent of cross-link density and concentration. Previous studies report that poly(propargyl-l-glutamate) (PPLG), synthesized by ring-opening polymerization of the N-carboxy anhydride of γ-propargyl-l-glutamate (γplglu), adopts a rigid a-helix conformation: we hypothesized that a random copolymer (PPDLG) with equal amounts of γplglu and γ-propargyl-d-glutamate (γpdglu) monomers would exhibit a more flexible random coil conformation. The resulting macromers exhibited narrow molecular weight distributions (PDI = 1.15) and were grafted with ethylene glycol groups using a highly efficient "click" azide/alkyne cycloaddition reaction with average grafting efficiency of 97% for PPLG and 85% for PPDLG. The polypeptide secondary structure, characterized via circular dichroism spectroscopy, FTIR spectroscopy, and dynamic light scattering, is indeed dependent upon monomer chirality: PPLG exhibits an α-helix conformation while PPDLG adopts a random coil conformation. Hydrogel networks produced by cross-linking either helical or random coil polypeptides with poly(ethylene glycol) (PEG) were analyzed for amount of swelling, gelation efficiency, and permeability to a model protein. In addition, the elastic modulus of helical and coil polypeptide gels was determined by AFM indentation in fluid. Importantly, we found that helical and coil polypeptide gels exhibited similar swelling and permeability but different stiffnesses, which correspond to predictions from the theory of semi-flexible chains. This journal is
- Oelker, Abigail M.,Hammond, Paula T.,Morey, Shannon M.,Griffith, Linda G.
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p. 10887 - 10895,9
(2012)
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- Redefining Protein Interfaces within Protein Single Crystals with DNA
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Proteins are exquisite nanoscale building blocks: molecularly pure, chemically addressable, and inherently selective for their evolved function. The organization of proteins into single crystals with high positional, orientational, and translational order results in materials where the location of every atom can be known. However, controlling the organization of proteins is challenging due to the myriad interactions that define protein interfaces within native single crystals. Recently, we discovered that introducing a single DNA-DNA interaction between protein surfaces leads to changes in the packing of proteins within single crystals and the protein-protein interactions (PPIs) that arise. However, modifying specific PPIs to effect deliberate changes to protein packing is an unmet challenge. In this work, we hypothesized that disrupting and replacing a highly conserved PPI with a DNA-DNA interaction would enable protein packing to be modulated by exploiting the programmability of the introduced oligonucleotides. Using concanavalin A (ConA) as a model protein, we circumvent potentially deleterious mutagenesis and exploit the selective binding of ConA toward mannose to noncovalently attach DNA to the protein surface. We show that DNA association eliminates the major PPI responsible for crystallization of native ConA, thereby allowing subtle changes to DNA design (length, complementarity, and attachment position) to program distinct changes to ConA packing, including the realization of three novel crystal structures and the deliberate expansion of ConA packing along a single crystallographic axis. These findings significantly enhance our understanding of how DNA can supersede native PPIs to program protein packing within ordered materials.
- Han, Zhenyu,Mirkin, Chad A.,Partridge, Benjamin E.,Winegar, Peter H.
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- Effect of side-wall functionalisation of multi-walled carbon nanotubes on the thermo-mechanical properties of epoxy composites
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In this work, a novel functionalisation was carried out by grafting carboxyl-terminated poly(acrylonitrile-co-butadiene) on the side-walls of multi-walled carbon nanotubes to prepare MWCNT-g-CTBN. The functionalized nanotubes were characterized by XPS, Raman spectroscopy, and TGA and the surface morphology was analyzed by transmission electron microscopy. The dispersion behavior of the MWCNT/epoxy nanosuspension was carefully analyzed by transmission optical microscopy (TOM) and rheology. The MWCNT-g-CTBN was added to the diglycidyl ether of bisphenol A-type epoxy to prepare MWCNT-g-CTBN/epoxy composites. Incorporation of CTBN-grafted MWCNTs in epoxy matrix imparted tremendous improvement in mechanical strength as well as fracture toughness when compared with pristine MWCNT/epoxy composites. The mechanism for this improvement in mechanical properties is attributed to the increase in interfacial strength between nanotubes and the epoxy matrix through chemical bonding. The toughening mechanism that leads to the enhancement in the fracture toughness of the nanocomposites was assessed with the help of Field Emission Scanning Electron Microscopy (FESEM). Dynamic mechanical analysis of the MWCNT-g-CTBN/epoxy composite revealed an increase in the Tg of the epoxy phase as well as an increase in modulus due to the enhancement in stiffness of the material.
- Konnola, Raneesh,Joseph, Kuruvilla
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- A convergent synthesis of heterocyclic dendrimers using the 1,3-dipolar cycloaddition reaction of organic azides and acetylenedicarboxylate esters
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The convergent synthesis of heterocyclic dendrimers using 1,3-dipolar cycloaddition reaction of organic azides and acetylenedicarboxylate esters was discussed. It was found that the second generation dibromofumarate was prepared from monomer and the first
- Van Wuytswinkel, Grete,Verheyde, Bert,Compernolle, Frans,Toppet, Suzanne,Dehaen, Wim
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- Design, synthesis, and biological evaluation of proteolysis targeting chimeras (PRoTACS) for the dual degradation of IGF-1R and SrC
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A focused PROTAC library was developed to degrade both IGF-1R and Src proteins, which are associated with various cancers. PROTACs with IGF-1R and Src degradation potentials were synthesized by tethering different inhibitor warhead units and the E3 ligase (CRBN) recruiting-pomalidomide with various linkers. The designed PROTACs 12a–b inhibited the proliferation and migration of MCF7 and A549 cancer cells with low micromolar potency (1–5 μM) in various cellular assays.
- Lee, Jeeyeon,Lee, Na Keum,Manda, Sudhakar,Oh, Dong-Chan
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- Selectively Targeting and Differentiating Vancomycin-Resistant Staphylococcus aureus via Dual Synthetic Fluorescent Probes
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Many Staphylococcus bacteria are pathogenic and harmful to humans. Noticeably, some Staphylococcus, including vancomycin-resistant S. aureus (VRSA), have become notoriously resistant to antibiotics and have spread rapidly, becoming threats to public health. Here, we designed a dual fluorescent probe scheme combining siderophores and antibiotics as the guiding units to selectively target VRSA and vancomycin-sensitive S. aureus (VSSA) in complex bacterial samples. Siderophore-mediated iron uptake is the key pathway by which S. aureus acquires iron in limited environments. Therefore, the siderophore-derivative probe could differentiate between S. aureus and other bacteria. Moreover, by fine-tuning the vancomycin-derivative probes, we could selectively target only VSSA, further differentiating VRSA and VSSA. Finally, by combining the siderophore-derivative probe and the vancomycin-derivative probe, we successfully targeted and differentiated between VRSA and VSSA in complicated bacterial mixtures.
- Wang, Tsung-Shing Andrew,Chen, Pin-Lung,Chen, Yi-Chen Sarah,Hung, Hsuan-Min,Huang, Jhih-Yi
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- Glyco-functionalized dinuclear rhenium(i) complexes for cell imaging
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The design, synthesis and photophysical characterization of four new luminescent glycosylated luminophores based on dinuclear rhenium complexes, namely Glyco-Re, are described. The derivatives have the general formula [Re2(μ-Cl)2(CO)
- Palmioli, Alessandro,Aliprandi, Alessandro,Septiadi, Dedy,Mauro, Matteo,Bernardi, Anna,De Cola, Luisa,Panigati, Monica
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- Hypoxia-Responsive19F MRI Probes with Improved Redox Properties and Biocompatibility
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19F magnetic resonance imaging (MRI), an emerging modality in biomedical imaging, has shown promise for in vitro and in vivo preclinical studies. Here we present a series of fluorinated Cu(II)ATSM derivatives for potential use as19F magnetic resonance agents for sensing cellular hypoxia. The synthesized complexes feature a hypoxia-targeting Cu2+ coordination core, nine equivalent fluorine atoms connected via a variable-length poly(ethylene glycol) linker. Introduction of the fluorine moiety maintains the planar coordination geometry of the Cu2+ center, while the linker length modulates the Cu2+/+ reduction potential,19F NMR relaxation properties, and lipophilicity. In particular, the19F NMR relaxation properties were quantitatively evaluated by the Solomon-Bloembergen model, revealing a regular pattern of relaxation enhancement tuned by the distance between Cu2+ and F atoms. Finally, the potential utility of these complexes for sensing reductive environments was demonstrated using both19F MR phantom imaging and19F NMR, including experiments in intact live cells.
- Xie, Da,Kim, Seyong,Kohli, Vikraant,Banerjee, Arnab,Yu, Meng,Enriquez, José S.,Luci, Jeffrey J.,Que, Emily L.
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- Spatially well-defined carbohydrate nanoplatforms: Synthesis, characterization and lectin interaction study
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Two novel dodecasubstituted carbohydrate nanoplatforms based on molecular Borromean rings and dodecaamine cages have been prepared for use in evaluating the importance of the spatial distribution of carbohydrates in their interaction with lectins. The binding affinities of the glyconanoplatforms were characterized using quartz crystal microbalance technology and compared with a monovalent reference and dodecaglycosylated fullerenes.
- Timmer,Flos, M. Abellán,J?rgensen, L. M?nster,Proverbio,Altun,Ramstr?m,Aastrup,Vincent
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- Synthesis and antifungal activities of N-glycosylated derivatives of Tunicyclin D, an antifungal octacyclopeptide
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A series of glycosylated derivatives of Tunicyclin D were synthesized through a highly efficient and versatile synthetic method. The method is based on solid-phase peptide synthesis using 2-chlorotrityl resin as the solid-phase support and glycosyl amino acids as building blocks. Biological studies of the synthetic Tunicyclin D derivatives showed monosaccharide-containing compounds exhibit improved or similar antifungal activities, whereas the compounds carrying disaccharide glycans, showed much weaker antifungal activities.
- Zhao, Qingjie,Zou, Yan,Guo, Junxiang,Yu, Shichong,Chai, Xiaoyun,Hu, Honggang,Wu, Qiuye
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- Process-tracing study on the post-assembly modification of poly-NHC-based metallosupramolecular cylinders with tunable aggregation-induced emission
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In this work, we demonstrate the design and fabrication of a series of cylinder-like, hexazido-terminated MI-CNHC (M = Ag, Au) complexes. Moreover, we present for the first time a process-tracing and aggregation-induced emission (AIE
- Wang, Yi-Shou,Bai, Sha,Wang, Yao-Yu,Han, Ying-Feng
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- Towards the simplification of protein synthesis: Iterative solid-supported ligations with concomitant purifications
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Please release me: A new linker for the temporary tagging of peptides at their N-terminus after solid-phase elongation, and its potential for capture/release purification is demonstrated. This concept is extended to a remarkably efficient self-purifying N-to-C iterative triazole ligation strategy, which is applied to the synthesis of a polypeptide having 160 residues, in a high purity without the need for chromatographic purification (see picture; orange blocks: peptide segments). Copyright
- Aucagne, Vincent,Valverde, Ibai E.,Marceau, Philippe,Galibert, Mathieu,Dendane, Nabil,Delmas, Agnès F.
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- Removal of GenX and Perfluorinated Alkyl Substances from Water by Amine-Functionalized Covalent Organic Frameworks
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Per- and polyfluorinated alkyl substances (PFAS), such as perfluorooctanoic acid (PFOA), perfluorooctanesulfonate (PFOS), and ammonium perfluoro-2-propoxypropionate (GenX), contaminate ground and surface waters throughout the world. The cost and performance limitations of current PFAS removal technologies motivate efforts to develop selective and high-affinity adsorbents. Covalent organic frameworks (COFs) are unexplored yet promising adsorbents because of their high surface area and tunable pore sizes. Here we show that imine-linked two-dimensional (2D) COFs bearing primary amines adsorb GenX rapidly at environmentally relevant concentrations. COFs with partial amine incorporation showed the highest capacity and fastest removal, suggesting that the synergistic combination of the polar group and hydrophobic surfaces are responsible for GenX binding. A COF with 28% amine loading also removed more than 90% of 12 out of 13 PFAS. These results demonstrate the promise of COFs for PFAS removal and suggest design criteria for maximizing adsorbent performance.
- Ji, Woojung,Xiao, Leilei,Ling, Yuhan,Ching, Casey,Matsumoto, Michio,Bisbey, Ryan P.,Helbling, Damian E.,Dichtel, William R.
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- Snap-top nanocarriers
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(Equation Presented). An approach to the design and fabrication of mechanized mesoporous silica nanoparticles is demonstrated at the proof of principle level. It relies on the reductive cleavage of disulfide bonds within an integrated nanosystem, wherein surface-bound rotaxanes incorporate disulfide bonds in their stalks,-which are encircled by cucurbit[6]uril or α-cyclodextrin rings, until reductive chemistry is performed, resulting in the snapping of the stalks of the rotaxanes, leading to cargo release from the inside of the nanoparticles.
- Ambrogio, Michael W.,Pecorelli, Travis A.,Patel, Kaushik,Khashab, Niveen M.,Trabolsi, Ali,Khatib, Hussam A.,Botros, Youssry Y.,Zink, Jeffrey I.,Stoddart, J. Fraser
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- Supramolecular compound nano-carrier as well as preparation method and application thereof
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The invention discloses a supramolecular compound nano-carrier as well as a preparation method and application thereof, and relates to the technical field of polymer chemistry and biological detection engineering. According to the supramolecular compound nano-carrier disclosed by the invention, a two-dimensional nanosheet supramolecular structure system generated by self-assembly is driven by an anion induction effect, and a supramolecular compound nano-carrier is of a single-layer nanosheet supramolecular structure constructed by a highly-oriented one-dimensional nanorod. A hydrophobic perylene group part is used as a skeleton part for constructing the highly-oriented one-dimensional nanorod, and the charge density of a single-layer nanosheet can be regulated and controlled. The surface of the water-soluble multivalent hydrophilic part can be loaded with DNAzyme deoxyribozyme for specific detection of heavy metal ions through electrostatic interaction, and the water-soluble multivalent supramolecular compound nano sensor is constructed. Based on a fluorescence change mechanism caused by specific cutting of heavy metal ions, The fluorescence detection of the heavy metal ions in food and biological tissues is realized, and the detection effect of the heavy metal ions is greatly enhanced.
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Paragraph 0068; 0083
(2021/08/14)
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- Sialyltransferase Inhibitors Suppress Breast Cancer Metastasis
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We report the synthesis and evaluation of a series of cell-permeable and N- versus O-selective sialyltransferase inhibitors. Inhibitor design entailed the functionalization of lithocholic acid at C(3) and at the cyclopentane ring side chain. Among the series, FCW34 and FCW66 were shown to inhibit MDA-MB-231 cell migration as effectively as ST3GALIII-gene knockdown did. FCW34 was shown to inhibit tumor growth, reduce angiogenesis, and delay cancer cell metastasis in animal models. Furthermore, FCW34 inhibited vessel development and suppressed angiogenic activity in transgenic zebrafish models. Our results provide clear evidence that FCW34-induced sialyltransferase inhibition reduces cancer cell metastasis by decreasing N-glycan sialylation, thus altering the regulation of talin/integrin/FAK/paxillin and integrin/NFκB signaling pathways.
- Fu, Chih-Wei,Tsai, Han-En,Chen, Wei-Sheng,Chang, Tzu-Ting,Chen, Chia-Ling,Hsiao, Pei-Wen,Li, Wen-Shan
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supporting information
p. 527 - 542
(2021/01/13)
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- A dansyl-derivatized phytic acid analogue as a fluorescent substrate for phytases: experimental and computational approach
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A new myo-inositol pentakisphosphate was synthesized, which featured a dansyl group at position C-5. The fluorescent tag was removed from the inositol by a 6-atom spacer to prevent detrimental steric interactions in the catalytic site of phytases. The PEG linker was used in order to enhance hydrophilicity and biocompatibility of the new artificial substrate. Computational studies showed a favorable positioning in the catalytic site of phytases. Enzymatic assays demonstrated that the tethered myo-inositol was processed by two recombinant phytases Phy-A and Phy-C, classified respectively as acid and alkaline phytases, with similar rates of phosphate release compared to their natural substrate.
- Dussouy, Christophe,Dubreucq, Eric,Chemardin, Patrick,Perrier, Véronique,Abadie, Josiane,Quiquampoix, Hervé,Plassard, Claude,Behr, Jean-Bernard
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supporting information
(2021/03/22)
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- Discovery of a new class of PROTAC BRD4 degraders based on a dihydroquinazolinone derivative and lenalidomide/pomalidomide
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BRD4 has emerged as an attractive target for anticancer therapy. However, BRD4 inhibitors treatment leads to BRD4 protein accumulation, together with the reversible nature of inhibitors binding to BRD4, which may limit the efficacy of BRD4 inhibitors. To address these problems, a protein degradation strategy based on the proteolysis targeting chimera (PROTAC) technology has been developed to target BRD4 recently. Herein, we present our design, synthesis and biological evaluation of a new class of PROTAC BRD4 degraders, which were based on a potent dihydroquinazolinone-based BRD4 inhibitor compound 6 and lenalidomide/pomalidomide as ligand for E3 ligase cereblon. Gratifyingly, several compounds showed excellent inhibitory activity against BRD4, and high anti-proliferative potency against human monocyte lymphoma cell line THP-1. Especially, compound 21 (BRD4 BD1, IC50 = 41.8 nM) achieved a submicromolar IC50 value of 0.81 μM in inhibiting the growth of THP-1 cell line, and was 4 times more potent than compound 6. Moreover, the mechanism study established that 21 could effectively induce the degradation of BRD4 protein and suppression of c-Myc. All of these results suggested that 21 was an efficacious BRD4 degrader for further investigation.
- Zhang, Fangqing,Wu, Zhenwei,Chen, Pan,Zhang, Jian,Wang, Tao,Zhou, Jinpei,Zhang, Huibin
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- Development of small-molecule BRD4 degraders based on pyrrolopyridone derivative
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Bromodomain-containing protein 4 (BRD4) plays a crucial role in the epigenetic regulation of gene transcription and some BRD4 inhibitors have been advanced to clinical trials. Nevertheless, the clinical application of BRD4 inhibitors could be limited by drug resistance. As an alternative strategy, the emerging Proteolysis Targeting Chimeras (PROTACs) technology has the potential to overcome the drug resistance of traditional small-molecule drugs. Based on PROTACs approaches, several BRD4 degraders were developed and have been proved to degrade BRD4 protein and inhibit tumor growth. Herein, we present the design, synthesis, and biological evaluation of pyrrolopyridone derivative-based BRD4 degraders. Four synthesized compounds displayed comparative potence against BRD4 BD1 with IC50 at low nanomolar concentrations. Anti-proliferative activity of 32a against BxPC3 cell line (IC50 = 0.165 μM) was improved by about 7-fold as compared to the BRD4 inhibitor ABBV-075. Furthermore, degrader 32a potently induced the degradation of BRD4 and inhibited the expression of c-Myc in BxPC3 cell line in a time-dependent manner. The exploration of intracellular antitumor mechanism showed 32a induced cell cycle arrest and apoptosis effectively. All the results demonstrated that compound 32a could be considered as a potential BRD4 degrader for further investigation.
- Chen, Pan,Wang, Lixun,Wang, Tao,Xu, Changliang,Zhang, Huibin,Zhang, Jian,Zheng, Peiyuan,Zhou, Jinpei,Zhu, Peiyu
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- Synthesis of: N -acetylglucosamine and N -acetylallosamine resorcinarene-based multivalent β-thio-glycoclusters: Unexpected affinity of N -acetylallosamine ligands towards Wheat Germ Agglutinin
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Herein, we report the synthesis of calix[4]resorcinarene-based multivalent ligands bearing β-S-GlcNAc and β-S-AllNAc recognition elements. A clickable β-S-AllNAc derivative was successfully prepared from a β-thioalkynyl GlcNAc precursor, making use of a 2,3-oxazoline intermediate, easily formed by intramolecular displacement of a triflate group located at the 3-position by the 2-N-acetate group. By reaction of these alkynyl-functionalized derivatives with an octaazido-calix[4]resorcinarene macrocycle having undecyl chains, two octavalent glycoclusters exposing the epimeric N-acetylhexosamines were obtained. In addition, a related calix[4]resorcinarene-based glycocluster having methyl groups instead of undecyl chains and β-S-GlcNAc residues was also synthesized. After an initial evaluation of the interaction of the undecyl-functionalized β-S-GlcNAc octavalent derivative with Wheat Germ Agglutinin (WGA) by a turbidimetry experiment, the interaction of the three synthesized glycoclusters towards WGA was studied by Isothermal Titration Calorimetry. The results showed a favorable effect due to the presence of the undecyl chains in terms of affinity. Surprisingly, the β-S-AllNAc octavalent compound showed the highest affinity among the evaluated glycoclusters, showing for the first time that WGA interacts with β-AllNAc-bearing ligands. Molecular docking studies of β-AllNAc with WGA in comparison with β-GlcNAc contributed to the understanding of the atomic interactions responsible for this unexpected affinity.
- Cagnoni, Alejandro J.,Cristófalo, Alejandro E.,Uhrig, María Laura
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supporting information
p. 6853 - 6865
(2020/10/02)
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- MONOMER AND MULTIMERIC ANTI-HBV AGENTS
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The present invention is directed to compounds, compositions and methods for preventing, treating or curing hepatitis B (HBV) infection in human subjects or other animal hosts. The compounds are as also pharmaceutically acceptable, salts, prodrugs, and other derivatives thereof as pharmaceutical compositions and methods for treatment, prevention or eradication of HBV infection.
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Page/Page column 143; 202-203
(2020/05/15)
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- Flavone derivative for treating tumor and application thereof
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The invention provides a flavone derivative represented by a formula I and pharmaceutically acceptable salt, hydrate or solvate thereof. In the formula I, R1 H, is 1-4 alkyl, amino or C1-4 acyl; R2 isisopentenyl or 2-hydroxy isopentyl; R3 is H, methyl or deuterated methyl; R4 represents C1-4 alkyl, amino or C1-4 acyl or R5 represents monosaccharide residue or oligosaccharide residue; and L represents polypeptide, C1-C20 straight chain alkyl or derivative thereof, C1-C20 straight chain or branched chain acyl derivative, C1-C20 ethylene glycol or derivative thereof, wherein Y is an integer of 0to 100, b is an integer of 1 to 100, C is an integer of 1 to 10, d is an integer of 0 to 100, and e is an integer of 0 to 100. The flavone derivative has high-efficiency broad-spectrum anticancer activity.
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Paragraph 0078-0080
(2020/09/16)
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- CBX8 CHROMDOMAIN INHIBITORS AND THE USES THEREOF
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The present invention relates to series of peptidomimetic compounds selectively targeting CBX8 of polycomb chromobox protein homolog proteins. Pharmaceutical compositions of those compounds and methods of using them in the treatment of diseases involved CBX8 pharmacology, including various cancers and leukemia, by administering therapeutically effective amounts of such compound alone or together with other therapeutics, are within the scope of this disclosure.
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Paragraph 0255
(2020/12/20)
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- PYRIDAZINE DERIVATIVES AS SMARCA2/4 DEGRADERS
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The present invention provides pyridazine derivatives of formula (I), which are therapeutically useful as SMARCA2/4 degraders. These compounds are useful in the treatment and/or prevention of diseases or disorders dependent upon SMARCA2/4 in a mammal. The present invention also provides preparation of the compounds and pharmaceutical compositions comprising at least one of the pyridazine derivatives of formula (I) or a pharmaceutically acceptable salt, or a stereoisomer thereof.
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Page/Page column 106
(2019/11/12)
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- EXENATIDE MODIFIER AND USE THEREOF
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Disclosed are an exenatide modifier for connecting the exenatide to a fatty chain with a carboxy in the terminus thereof by means of a hydrophilic connecting arm, and a use thereof in preparing drugs serving as a GLP-1 receptor agonist; a use in preparing drugs for preventing and/or treating diseases and/or symptoms associated with a low GLP-1 receptor activity; a use in preparing drugs for diseases and/or symptoms associated with glycometabolism; a use in preparing drugs for diabetes; a use in preparing drugs for fatty liver disease, and a use in preparing drugs for losing weight.
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Paragraph 0237
(2018/05/24)
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- Clickable prodrugs bearing potent and hydrolytically cleavable nicotinamide phosphoribosyltransferase inhibitors
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Purpose: Our previous study indicated that carborane containing small-molecule 1-(hydroxymethyl)-7-(4′-(trans-3″-(3′″-pyridyl)acrylamido)butyl)-1,7-dicarbadodecaborane (hm-MC4-PPEA), was a potent inhibitor of nicotinamide phosphoribosyltransferase (Nampt)
- Sadrerafi, Keivan,Mason, Emilia O.,Lee, Mark W.
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p. 987 - 995
(2018/05/07)
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- COMPOUNDS USEFUL FOR TREATING GASTROINTESTINAL TRACT DISORDERS
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The present disclosure is directed to compounds and methods for the treatment of disorders associated with fluid retention or salt overload, such as heart failure (in particular, congestive heart failure), chronic kidney disease, end-stage renal disease, liver disease, and peroxisome proliferator-activated receptor (PPAR) gamma agonist- induced fluid retention. The present disclosure is also directed to compounds and methods for the treatment of hypertension. The present disclosure is also directed to compounds and methods for the treatment of gastrointestinal tract disorders, including the treatment or reduction of pain associated with gastrointestinal tract disorders.
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Paragraph 0442
(2018/07/31)
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- INHIBITORS OF NHE-MEDIATED ANTIPORT
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The present disclosure is directed to compounds (Ι') and to their use in methods for the treatment of disorders associated with fluid retention or salt overload, such as heart failure (in particular, congestive heart failure), chronic kidney disease, end-stage renal disease, liver disease, and peroxisome proliferator-activated receptor (PPAR) gamma agonist-induced fluid retention. The present disclosure is also directed to compounds (Ι') and their use in methods for the treatment of hypertension. The present disclosure is also directed to compounds (Ι') and to their use in methods for the treatment of gastrointestinal tract disorders, including the treatment or reduction of pain associated with gastrointestinal tract disorders.
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Paragraph 00296
(2018/07/31)
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- Intracellular Protein-Labeling Probes for Multicolor Single-Molecule Imaging of Immune Receptor-Adaptor Molecular Dynamics
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Single-molecule imaging (SMI) has been widely utilized to investigate biomolecular dynamics and protein-protein interactions in living cells. However, multicolor SMI of intracellular proteins is challenging because of high background signals and other lim
- Sato, Ryota,Kozuka, Jun,Ueda, Masahiro,Mishima, Reiko,Kumagai, Yutaro,Yoshimura, Akimasa,Minoshima, Masafumi,Mizukami, Shin,Kikuchi, Kazuya
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supporting information
p. 17397 - 17404
(2017/12/15)
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- Novel compound 2-amino-2-(1-(2-(2-hydroxyethoxy)ethyl)-1H-1,2,3-triazol-4-yl)propane-1,3-diol and use thereof
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The present invention relates to a novel compound 2-amino-2-(1-(2-(2-hydroxyethoxy)ethyl)-1H-1,2,3-triazol-4-yl)propane-1,3-diol derivative represented by chemical formula 1 and uses thereof. The novel compound represented by chemical formula 1 of the present invention is effective in inhibiting ASM and has an excellent treatment effect such as reduction in Aandbeta; plaque in Alzheimerandprime;s brain environments, improvement in memory and anxiety and alleviation of neurogenic inflammation, thereby being usefully used for preventing neurodegenerative disorders including Alzheimerandprime;s disease and depression, or developing medicines and having excellent industrial applicability.COPYRIGHT KIPO 2018
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Paragraph 0201; 0206; 0213; 0214; 0215
(2018/04/20)
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- Multimeric xanthates as carbonic anhydrase inhibitors
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The field of multivalent inhibition of enzymes is growing exponentially from the first reported multivalent effect on a glycosidase enzyme. However, the investigations have generally remained restricted to carbohydrate-processing enzymes. Carbonic anhydrases are ubiquitous metallo-enzymes involved in many key biological processes, that catalyze the reversible hydration/dehydration of CO2/HCO3. This study reports the first synthesis of multimeric xanthates addressing the selectivity and potency of CA multivalent inhibition. Six multivalent compounds containing three, four, and six xanthate moieties were prepared and assayed against four relevant CA isoforms together with their monovalent analogues. Some of the multimers were stronger inhibitors than the monomeric species. For hCA I, the two best molecules 18 and 20 showed an improvement of the ligand affinity of 4.8 and 2.3 per xanthate units (valence-corrected values), respectively, which corresponds to a clear multivalent effect. Moreover, the biochemical assays demonstrated that the multimeric presentation of xanthates, also affected the selectivity of the relative inhibition among the four CAs assayed.
- Abellán-Flos, Marta,Tan?, Muhammet,Supuran, Claudiu T.,Vincent, Stéphane P.
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p. 946 - 952
(2016/10/09)
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- LIGAND-MODIFIED DOUBLE-STRANDED NUCLEIC ACIDS
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The invention provides for double stranded nucleic acid molecules comprising a 5 'extension of the sense or antisense strand and further comprising a plurality of nucleotides that are conjugated to a ligand and methods of using the double-stranded nucleic acid molecules. Ligand-modified oligomers where the sense stands form a tetraloop provide new potent and stable RNA interference agents. These dsNA molecules are synthesized using a plurality of nucleotides that include ligand-modified monomers, nucleotide analog monomers, modified nucleotide monomers and the like, using standard nucleotide synthetic methods and systems.
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Paragraph 00653
(2016/07/05)
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- Glycosylation near infrared dye as well as preparation method and application thereof
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The invention discloses glycosylation near infrared dye as well as a preparation method and application thereof, in particular relates to dye shown as a general formula I. The dye is finally obtained by respective synthesis of three fragments and substitution and condensation reaction. The dye has the functions of ultraviolet absorption and near-infrared emission, is easy for detection and has a derivatization site which can be used for connecting molecules with different target abilities. In addition, the dye is also provided with a fluorescent switch which can be used for connecting anoxia, pH, enzyme and redox sensitive groups, so that the effect of selectively fluorescing is realized; the dye is applied to visualized target administration (see the description).
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Paragraph 0033; 0034; 0035; 0036; 0037
(2016/10/10)
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- PEPTIDE CONTAINING CONJUGATES FOR DUAL MOLECULAR DELIVERY OF OLIGONUCLEOTIDES
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Disclosed herein is a peptide containing conjugate comprising (P)c-(L)d-(G)e, wherein P is a peptide and each occurance of P is independently selected from Table 2; L is an optional linker and each occurance of L, if prese
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Page/Page column 84; 85; 86
(2015/05/26)
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- DUAL MOLECULAR DELIVERY OF OLIGONUCLEOTIDES AND PEPTIDE CONTAINING CONJUGATES
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Disclosed herein is a method for inhibiting expression of a gene of a subject comprising administering (1) a composition comprising R-(L)a-(G)b; wherein R is an oligonucleotide selected from the group consisting of DNA, RNA, siRNA, and microRNA; L is a li
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Page/Page column 85; 86; 87
(2015/05/26)
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- BCR-ABL TYROSINE-KINASE LIGANDS CAPABLE OF DIMERIZING IN AN AQUEOUS SOLUTION, AND METHODS OF USING SAME
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Described herein are monomers capable of forming a biologically useful multimer when in contact with one, two, three or more other monomers in an aqueous media. In one aspect, such monomers may be capable of binding to another monomer in an aqueous media (e.g. invivo) to form a multimer (e.g. a dimer). Contemplated monomers may include a ligand moiety, a linker element, and a connector element that joins the ligand moiety and the linker element. In an aqueous media, such contemplated monomers may join together via each linker element and may thus be capable of modulating one or more biomolecules substantially simultaneously, e.g., modulate two or more binding sites on a Bcr-Abl tyrosine kinase.
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Paragraph 00442; 00457; 00458
(2015/07/23)
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- Exploring carbonic anhydrase inhibition with multimeric coumarins displayed on a fullerene scaffold
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Carbonic anhydrases (CAs) are ubiquitous Zn metallo-enzymes that catalyze the reversible hydration/dehydration of CO2/HCO3-. CAs are involved in many key biological processes, therefore their inhibition has become an attractive research field. Distinct families of CA inhibitors (CAIs) have been reported, most of them interacting with the Zn(ii) at the active site. Some compounds such as the coumarins are hydrolyzed before binding the entrance of the active site cavity, and thus behave as "suicide" inhibitors. This study reports the first synthesis of multimeric suicide inhibitors, designed to address the selectivity and the potency of CA multivalent inhibition. Twelve coumarin units have been grafted to a central fullerene scaffold thanks to a CuAAC reaction and the final dodecamers were assayed against 4 relevant CAs. The multimers were always stronger inhibitors than the monomeric species but no strong "multivalent effect" was found. However, our study showed that the multimeric presentation of the coumarin around the C60, indeed affected the selectivity of the relative inhibition among the 4 CAs assayed.
- Abellán-Flos, Marta,Tan?, Muhammet,Supuran, Claudiu T.,Vincent, Stéphane P.
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supporting information
p. 7445 - 7451
(2015/11/27)
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- Effect of electron donating groups on polyphenol-based antioxidant dendrimers
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Numerous studies have reported the beneficial effects of antioxidants in human diseases. Among their biological effects, a majority of antioxidants scavenge reactive radicals in the body, thereby reducing oxidative stress that is associated with the patho
- Lee, Choon Young,Nanah, Cyprien N.,Held, Rich A.,Clark, Amanda R.,Huynh, Uyen G.T.,Maraskine, Marina C.,Uzarski, Rebecca L.,McCracken, John,Sharma, Ajit
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p. 125 - 134
(2015/03/18)
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- SULFORAPHANE-DERIVED COMPOUNDS, PRODUCTION METHOD THEREOF AND THE MEDICAL, FOOD AND COSMETIC USE OF SAME
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The present invention relates to a new series of compounds having general formula (I) and the optical isomer or enantiomer forms thereof, which belong to the family of sulforaphane derivatives. The invention also relates to the production method thereof. The invention further relates to the multiple medical (pharmaceutical, homeopathic and phytotherapeutic), food, cosmetic and dietary uses of said series of compounds, especially the use thereof in the prevention and/or treatment of diseases and any type of illness or damage associated with an oxidative process or which, although not involved in said process, are mediated by the Nrf2 transcription factor, such as, for example, cancer. The compounds can be used alone or, alternatively, encapsulated in cyclodextrins.
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Paragraph 0077-0081
(2015/03/16)
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- SULFORAPHANE-DERIVED COMPOUNDS, PRODUCTION METHOD THEREOF AND THE MEDICAL, FOOD AND COSMETIC USE OF SAME
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The present invention relates to a new series of compounds having general formula (I) and the optical isomer or enantiomer forms thereof, which belong to the family of sulforaphane derivatives. The invention also relates to the production method thereof. The invention further relates to the multiple medical (pharmaceutical, homeopathic and phytotherapeutic), food, cosmetic and dietary uses of said series of compounds, especially the use thereof in the prevention and/or treatment of diseases and any type of illness or damage associated with an oxidative process or which, although not involved in said process, are mediated by the Nrf2 transcription factor, such as, for example, cancer. The compounds can be used alone or, alternatively, encapsulated in cyclodextrins.
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Paragraph 0084-0088
(2015/04/28)
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- Design and synthesis of protoporphyrin IX/vitamin B12 molecular hybrids via CuAAC reaction
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The design and synthesis of new molecular hybrids composed of protoporphyrin IX (PPIX) and vitamin B12 via copper catalyzed alkyne azide cycloaddition reaction is described. New, clickable aminoazide and aminoalkyne linkers were prepared and subsequently attached to PPIX (via vinyl group) and to vitamin B12 giving desired building blocks. Preliminary results showed that respective water soluble hybrids were formed under CuAAC reaction. Gratifyingly, Cu incorporation into the PPIX core was avoided, which was important for further biological studies. Copyright
- Loska, Rafa?,Janiga, Anita,Gryko, Dorota
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p. 104 - 117
(2013/04/23)
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- Synthesis of novel, fluorescently tagged analogs of glycosylphosphatidylinositol (GPI) anchors
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Glycosylphosphatidylinositol (GPI) anchors are a group of complex glycolipids that attach extracellular proteins and glycoproteins to the eukaryotic cell outer membrane. To better understand GPI anchorage, it is necessary to have access to homogeneous, structurally defined, and functionalized GPIs and GPI analogs. In this regard, chemical synthesis is necessary, as GPI anchors are rather scarce and heterogeneous in natural sources. Three GPI analogs with phosphoglycerolipids linked to the pseudodisaccharide core and their fluorescein conjugates were prepared in this work as a small tool set useful for probing how the lipid composition and carbohydrate anomeric configuration may affect the properties of GPI anchors.
- Johnson, Charles L.,Guo, Zhongwu
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p. 301 - 323
(2013/10/08)
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- NOVEL TETRAGALNAC CONTAINING CONJUGATES AND METHODS FOR DELIVERY OF OLIGONUCLEOTIDES
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Disclosed herein is a modular composition comprising 1) an oligonucleotide; 2) one or more tetraGalNAc ligands of Formula (I), which may be the same or different; optionally, 3) one or more linkers, which may be the same or different; and optionally, 4) o
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Page/Page column 29-30
(2013/11/19)
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- NOVEL TETRAGALNAC AND PEPTIDE CONTAINING CONJUGATES AND METHODS FOR DELIVERY OF OLIGONUCLEOTIDES
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Disclosed herein is a modular composition comprising 1) an oligonucleotide; 2) one or more tetraGalNAc ligands of Formula (I), which may be the same or different; optionally, 3) one or more linkers, which may be the same or different; 4) one or more peptides independently selected from Table 3, which may be the same or different; and optionally, 5) one or more targeting ligands, solubilizing agents, pharmacokinetics enhancing agents, lipids, and/or masking agents.
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Page/Page column 76-77
(2013/11/19)
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- SHORT INTERFERING NUCLEIC ACID (siNA) COMPOSITIONS
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The present invention relates to compounds, compositions, and methods for the study, diagnosis, and treatment of traits, diseases and conditions that respond to the modulation of gene expression and/or activity, and/or modulate a gene expression pathway.
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Page/Page column 112
(2013/11/19)
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- A new strategy for intracellular delivery of enzyme using mesoporous silica nanoparticles: Superoxide dismutase
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We developed mesoporous silica nanoparticle (MSN) as a multifunctional vehicle for enzyme delivery. Enhanced transmembrane delivery of a superoxide dismutase (SOD) enzyme embedded in MSN was demonstrated. Conjugation of the cell-penetrating peptide derive
- Chen, Yi-Ping,Chen, Chien-Tsu,Hung, Yann,Chou, Chih-Ming,Liu, Tsang-Pai,Liang, Ming-Ren,Chen, Chao-Tsen,Mou, Chung-Yuan
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supporting information
p. 1516 - 1523
(2013/03/29)
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- Photothermal-responsive [2]rotaxanes
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Three photothermal-responsive α-cyclodextrin-based [2]rotaxanes were prepared via the copper(i)-catalyzed azide-alkyne cycloaddition, in which the α-cyclodextrin ring was threaded onto the azobenzene dumbbell component. The difference between the three [2]rotaxanes are the length of the ethylene glycol repeating chains connected between the azobenzene and triazole units in the dumbbell components. The α-cyclodextrin rings in the [2]rotaxanes can be reversibly switched between the azobenzene unit and triazole/ethylene glycol unit driven by the trans-cis isomerization of the azobenzene unit. The trans-to-cis isomerization of the azobenzene unit under UV light irradiation (365 nm) leads the α-cyclodextrin ring moving to the triazole/ethylene glycol unit, while the cis-to-trans isomerization of the azobenzene unit under either visible light irradiation or heating enables the α-cyclodextrin ring shuttling back to the azobenzene station. The different ethylene glycol repeating chains in the [2]rotaxanes can affect (1) the isomerization rates of the azobenzene units, i.e. the longer the chain, the faster the isomerization rate, and (2) fluorescent quantum yields of the [2]rotaxanes, i.e. the longer the chain, the lower the fluorescent quantum yield. In addition, the quantum yields of the [2]rotaxanes were enhanced by UV light irradiation and decreased back upon visible light irradiation or heating at 65 °C. The current research provides a fundamental understanding of the working mechanism for photothermal-responsive [2]rotaxanes.
- Yan, Hong,Zhu, Liangliang,Li, Xing,Kwok, Anna,Li, Zin,Agren, Hans,Zhao, Yanli
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p. 2341 - 2350
(2013/03/14)
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- Functional mesoporous silica nanoparticles for photothermal-controlled drug delivery in vivo
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Release me! A new class of photothermal-responsive [2]rotaxane-appended mesoporous silica nanoparticles (MSNPs) was developed. Remote-controlled movement of the α-cyclodextrin ring (green) upon trans-cis isomerization of the azobenzene axle (red) enables the loading and release of drugs on demand (see scheme). Curcumin-loaded MSNPs were shown to release curcumin into zebrafish larvae upon treatment with visible light or heat. Copyright
- Yan, Hong,Teh, Cathleen,Sreejith, Sivaramapanicker,Zhu, Liangliang,Kwok, Anna,Fang, Weiqin,Ma, Xing,Nguyen, Kim Truc,Korzh, Vladimir,Zhao, Yanli
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supporting information; scheme or table
p. 8373 - 8377
(2012/09/07)
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- COMPOUNDS AND METHODS FOR PURIFYING PEPTIDES PRODUCED BY SOLID PHASE PEPTIDE SYNTHESIS
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The invention relates to compounds which can be used for purifying peptides produced by solid phase peptide synthesis. In addition, the invention relates to methods for purifying peptides produced by solid phase peptide synthesis using the compounds accor
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- Helix versus coil polypeptide macromers: Gel networks with decoupled stiffness and permeability
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As a platform for investigating the individual effects of substrate stiffness, permeability, and ligand density on cellular behavior, we developed a set of hydrogels with stiffness tuned by polymer backbone rigidity, independent of cross-link density and concentration. Previous studies report that poly(propargyl-l-glutamate) (PPLG), synthesized by ring-opening polymerization of the N-carboxy anhydride of γ-propargyl-l-glutamate (γplglu), adopts a rigid a-helix conformation: we hypothesized that a random copolymer (PPDLG) with equal amounts of γplglu and γ-propargyl-d-glutamate (γpdglu) monomers would exhibit a more flexible random coil conformation. The resulting macromers exhibited narrow molecular weight distributions (PDI = 1.15) and were grafted with ethylene glycol groups using a highly efficient "click" azide/alkyne cycloaddition reaction with average grafting efficiency of 97% for PPLG and 85% for PPDLG. The polypeptide secondary structure, characterized via circular dichroism spectroscopy, FTIR spectroscopy, and dynamic light scattering, is indeed dependent upon monomer chirality: PPLG exhibits an α-helix conformation while PPDLG adopts a random coil conformation. Hydrogel networks produced by cross-linking either helical or random coil polypeptides with poly(ethylene glycol) (PEG) were analyzed for amount of swelling, gelation efficiency, and permeability to a model protein. In addition, the elastic modulus of helical and coil polypeptide gels was determined by AFM indentation in fluid. Importantly, we found that helical and coil polypeptide gels exhibited similar swelling and permeability but different stiffnesses, which correspond to predictions from the theory of semi-flexible chains.
- Oelker, Abigail M.,Morey, Shannon M.,Griffith, Linda G.,Hammond, Paula T.
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p. 10887 - 10895
(2013/01/15)
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- Design and synthesis of a dual linker for solid phase synthesis of oleanolic acid derivatives
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A hydrophilic amino-terminated poly(ethylene glycol)-type dual linker for solid phase synthesis of oleanolic acid derivatives using trityl chloride resin was designed and synthesized for the first time. Model reactions in both liquid and solid phase were performed to show the feasibility of its selective cleavage at two different sites. The biological assay results indicated that the long and flexible alkyl ether functionality in the linker is less likely to be critical for the binding event. Following the successful solid-phase synthesis of model compounds, the potential of this dual linker in reaction monitoring and target identification is deemed worthy of further study.
- Wang, Shaorong,Fang, Weishuo
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experimental part
p. 4748 - 4763
(2011/08/22)
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