- Conjugation of mono and di-GalNAc sugars enhances the potency of antisense oligonucleotides via ASGR mediated delivery to hepatocytes
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Antisense oligonucleotides (ASOs) conjugated to trivalent GalNAc ligands show 10-fold enhanced potency for suppressing gene targets expressed in hepatocytes. Trivalent GalNAc is a high affinity ligand for the asialoglycoprotein receptor (ASGR)—a C-type lectin expressed almost exclusively on hepatocytes in the liver. In this communication, we show that conjugation of two and even one GalNAc sugar to single stranded chemically modified ASOs can enhance potency 5–10 fold in mice. Evaluation of the mono- and di-GalNAc ASO conjugates in an ASGR binding assay suggested that chemical features of the ASO enhance binding to the receptor and provide a rationale for the enhanced potency.
- Kinberger, Garth A.,Prakash, Thazha P.,Yu, Jinghua,Vasquez, Guillermo,Low, Audrey,Chappell, Alfred,Schmidt, Karsten,Murray, Heather M.,Gaus, Hans,Swayze, Eric E.,Seth, Punit P.
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Read Online
- Lipase sensing by naphthalene diimide based fluorescent organic nanoparticles: a solvent induced manifestation of self-assembly
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The precise control of supramolecular self-assembly is gaining utmost interest for the demanding applications of manifested nano-architecture across the scientific domain. This study delineates the morphological transformation of naphthalene diimide (NDI) derived amphiphiles with varying water content in dimethyl sulfoxide (DMSO) and the selective sensing of lipase using its aggregation-induced emission (AIE) properties. To this end, NDI-based, benzyl alcohol protected alkyl chain (C1, C5, and C10) linked amphiphilic molecules (NDI-1,2,3) were synthesized. Among the synthesized amphiphiles, benzyl ester linked C5 tailored naphthalene diimide (NDI-2) exhibited AIE with an emission maximum at 490 nm in a DMSO-water binary solvent system fromfw= 30% and above water content. The fibrous morphology ofNDI-2atfw= 30% got gradually transformed to spherical aggregated particles along with steady increment in the emission intensity upon increasing the amount of water in DMSO. Atfw= 99% water in DMSO, complete transformation to fluorescent organic nanoparticles (FONPs) was observed. Microscopic and spectroscopic techniques demonstrated the solvent driven morphological transformation and the AIE property ofNDI-2. Moreover, this AIE ofNDI-2FONPs was employed in the selective turn-off sensing of lipase against many other enzymes including esterase, through hydrolysis of a benzyl ester linkage with a limit of detection 10.0 ± 0.8 μg L?1. TheNDI-2FONP also exhibited its lipase sensing efficiencyin vitrousing a human serum sample.
- Chakraborty, Debayan,Sarkar, Deblina,Ghosh, Anup Kumar,Das, Prasanta Kumar
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p. 2170 - 2180
(2021/03/14)
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- Novel bisubstrate uridine-peptide analogues bearing a pyrophosphate bioisostere as inhibitors of human O-GlcNAc transferase
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Protein O-linked β-D-N-acetylglucosamine (O-GlcNAc) modification (O-GlcNAcylation), an essential post-translational as well as cotranslational modification, is the attachment of β-D-N-acetylglucosamine to serine and threonine residues of nucleocytoplasmic proteins. An aberrant O-GlcNAc profile on certain proteins has been implicated in metabolic diseases such as diabetes and cancer. Inhibitors of O-GlcNAc transferase (OGT) are valuable tools to study the cell biology of protein O-GlcNAc modification. In this study we report novel uridine-peptide conjugate molecules composed of an acceptor peptide covalently linked to a catalytically inactive donor substrate analogue that bears a pyrophosphate bioisostere and explore their inhibitory activities against OGT by a radioactive hOGT assay. Further, we investigate the structural basis of their activities via molecular modelling, explaining their lack of potency towards OGT inhibition.
- Ryan, Philip,Shi, Yun,von Itzstein, Mark,Rudrawar, Santosh
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- Augmenting the efficacy of anti-cocaine catalytic antibodies through chimeric hapten design and combinatorial vaccination
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Given the need for further improvements in anti-cocaine vaccination strategies, a chimeric hapten (GNET) was developed that combines chemically-stable structural features from steady-state haptens with the hydrolytic functionality present in transition-state mimetic haptens. Additionally, as a further investigation into the generation of an improved bifunctional antibody pool, sequential vaccination with steady-state and transition-state mimetic haptens was undertaken. While GNET induced the formation of catalytically-active antibodies, it did not improve overall behavioral efficacy. In contrast, the resulting pool of antibodies from GNE/GNT co-administration demonstrated intermediate efficacy as compared to antibodies developed from either hapten alone. Overall, improved antibody catalytic efficiency appears necessary to achieve the synergistic benefits of combining cocaine hydrolysis with peripheral sequestration.
- Wenthur, Cody J.,Cai, Xiaoqing,Ellis, Beverly A.,Janda, Kim D.
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p. 3666 - 3668
(2017/07/27)
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- Using N-nitrosodichloroacetamides to conveniently convert linear primary amines into alcohols
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The reported rearrangement of N-nitrosodichloroacetamides provides a practicalmethod for converting primary amines into primary alcohols. The reaction sequence is operationally simple, requires only a single purification, and is compatible with a number of common functional groups. Mechanistic studies of the nitrosylation and rearrangement reactions illustrate the increased utility of dichloroacetamides compared to various other amides for this transformation.
- Macarthur, Nicholas S.,Wang, Linshu,Mccarthy, Blaine G.,Jakobsche, Charles E.
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supporting information
p. 2014 - 2021
(2015/08/18)
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- Method of Making 6-Aminocaproic Acid As Active Pharmaceutical Ingredient
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The present invention provides a method for making 6-aminocaproic acid as an active pharmaceutical ingredient. The method comprises: performing a hydrolysis procedure to have ε-caprolactam react with acid or base to generate a first reaction mixture, performing a modification procedure to have a solubility regulating agent reacts with 6-aminocaproic acid in the first reaction mixture to form a second reaction mixture including an aminocaproic acid intermediate, performing a separation procedure to have the intermediate separated from the second reaction mixture and performing a hydrogenation procedure to have the aminocaproic acid intermediate hydrogenated to form a 6-aminocaproic acid product.
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Paragraph 0055; 0057
(2014/02/16)
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- DRUG-LIGAND CONJUGATES, SYNTHESIS THEREOF, AND INTERMEDIATES THERETO
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The present invention relates to methods for synthesizing compounds of formula I or pharmaceutically acceptable salts thereof: I wherein each of X, Alk1, Alk2, and W are as defined and described herein.
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Paragraph 0648; 0649; 0650
(2013/07/31)
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- Probing active cocaine vaccination performance through catalytic and noncatalytic hapten design
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Presently, there are no FDA-approved medications to treat cocaine addiction. Active vaccination has emerged as one approach to intervene through the rapid sequestering of the circulating drug, thus terminating both psychoactive effects and drug toxicity. Herein, we report our efforts examining two complementary, but mechanistically distinct active vaccines, i.e., noncatalytic and catalytic, for cocaine treatment. A cocaine-like hapten GNE and a cocaine transition-state analogue GNT were used to generate the active vaccines, respectively. GNE-KLH (keyhole limpet hemocyannin) was found to elicit persistent high-titer, cocaine-specific antibodies and blunt cocaine-induced locomotor behaviors. Catalytic antibodies induced by GNT-KLH were also shown to produce potent titers and suppress locomotor response in mice; however, upon repeated cocaine challenges, the vaccine's protecting effects waned. In depth kinetic analysis suggested that loss of catalytic activity was due to antibody modification by cocaine. The work provides new insights for the development of active vaccines for the treatment of cocaine abuse.
- Cai, Xiaoqing,Whitfield, Timothy,Hixon, Mark S.,Grant, Yanabel,Koob, George F.,Janda, Kim D.
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p. 3701 - 3709
(2013/06/27)
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- Structural analysis of ARC-type inhibitor (ARC-1034) binding to protein kinase A catalytic subunit and rational design of bisubstrate analogue inhibitors of basophilic protein kinases
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The crystal structure of a complex of the catalytic subunit (type α) of cAMP-dependent protein kinase (PKA Cα) with ARC-type inhibitor (ARC-1034), the presumed lead scaffold of previously reported adenosineoligo-arginine conjugate-based (ARC-type) inhibitors, was solved. Structural elements important for interaction with the kinase were established with specifically modified derivatives of the lead compound. On the basis of this knowledge, a new generation of inhibitors, conjugates of adenosine-4′-dehydroxymethyl-4′-carboxylic acid moiety and oligo(D-arginine), was developed with inhibitory constants well into the subnanomolar range. The structural determinants of selectivity of the new compounds were established in assays with ROCK-II and PKBy.
- Lavogina, Darja,Lust, Marje,Viil, Indrek,K?nig, Norbert,Raidaru, Gerda,Rogozina, Jevgenia,Enkvist, Erki,Uri, Asko,Bossemeyer, Dirk
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supporting information; experimental part
p. 308 - 321
(2009/10/01)
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- PARAMAGNETIC METAL COMPLEXES FOR THE MRI VISUALIZATION OF INTERNALIZED POLYNUCLEOTIDES
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The invention relates to paramagnetic ion-based contrast agents that are positively charged at physiological pH and that bind non covalently to a polynucleotide chain for use in the preparation of a diagnostic formulation for the "in vivo" visualization of polynucleotides internalized into human or animal body cells by use of Magnetic Resonance Imaging techniques.
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Page/Page column 12; 25
(2008/06/13)
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