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Shinya Fujii, Shuichi Mori, Hiroyuki Kagechika, Marco Antonio Mendoza Parra, Hinrich Gronemeyer
Herein, we report the rational design, synthesis and biological evaluation of conjugates consisting of the synthetic retinoid Am580 and biotin connected via a linker moiety. We found that the linking substructure between the retinoid part and the biotin part is critical for retaining the biological activity. Conjugate 4 with a shorter linker showed similar potency to endogenous retinoid ATRA (1) and the parent compound Am580 (2) for neural differentiation of mouse embryotic carcinoma P19 cells, and showed the same pattern of induction of gene expression...
June 6, 2018: Bioorganic & Medicinal Chemistry Letters
Yan Li, Ying Ru Loh, Alvin W Hung, CongBao Kang
Zika virus (ZIKV) protease is a two-component complex in which NS3 contains the catalytic triad and NS2B cofactor region is important for protease folding and activity. A protease construct-eZiPro lacking the transmembrane domains of NS2B was designed. Structural study on eZiPro reveals that the Thr-Gly-Lys-Arg (TGKR) sequence at the C-terminus of NS2B binds to the active site after cleavage. Another bZiPro construct only contains NS2B cofactor region and the N-terminus of NS3 without any artificial linker or protease cleavage site, giving rise to an empty pocket accessible to substrate and inhibitor binding...
June 13, 2018: Biochemical and Biophysical Research Communications
Dillon T Flood, Jordi C J Hintzen, Michael J Bird, Philip A Cistrone, Jason S Chen, Philip E Dawson
Facile synthesis of C-terminal thioesters is integral to native chemical ligation (NCL) strategies for chemical protein synthesis. Here we introduce a new method of mild peptide activation, which leverages SPPS on an established resin linker and a classical heterocyclic chemistry to convert C-terminal peptide hydrazides to their corresponding thioesters via an acyl pyrazole intermediate. Peptide hydrazides, synthesized on established trityl chloride resins, can be activated in solution with stoichiometric acetyl acetone (acac), readily proceed to the peptide acyl-pyrazole...
June 16, 2018: Angewandte Chemie
Wathiq Sattar Abdul-Hassan, Denis Roux, Christophe Bucher, Saioa Cobo, Florian Molton, Eric Saint-Aman, Guy Royal
We report the study of stimuli-responsive Zn(II) and Fe(II) coordination polymers (MC34+ or MC24+ with M = Fe2+ or Zn2+). These soluble metallopolymers were formed spontaneously by reaction of an organic ligand (C34+ or C24+) with one molar equivalent of metal ions. The C34+ and C24+ ligands incorporate two chelating terpyridine groups bridged by a redox responsive hinge featuring two viologen units (viologen = N,N'-dialkyl-4,4'-bipyridinium) linked either through propyl (C34+) or ethyl (C24+) chains. The viologen units in the polymer chains were reduced (1e per viologen group) either by bulk electrolysis or by visible-light irradiation carried out in the presence of a photosensitizer...
June 15, 2018: Chemistry: a European Journal
Ryo Tsumura, Shino Manabe, Hiroki Takashima, Yoshikatsu Koga, Masahiro Yasunaga, Yasuhiro Matsumura
Antibody-drug conjugates (ADCs) are currently considered to be promising agents for cancer therapy. However, especially in solid tumors, the uneven distribution of ADCs would decrease their efficacy in clinical studies. We suggest that in addition to optimizing ADC components, such as the linker structure and anticancer agent, it is necessary to consider the distribution of the ADC within tumor tissue. In this study, we established three kinds of anti-tissue factor (TF) ADCs: 1849ADC with a low kd , 444ADC with an intermediate kd , and 1084ADC with a high kd ...
June 12, 2018: Journal of Controlled Release: Official Journal of the Controlled Release Society
Vanesa L Silvestri, Julie T Millard
Real time quantitative reverse transcription PCR was used to monitor changes in apoptotic gene expression after treating cells with the DNA cross-linkers epichlorohydrin (ECH) and diepoxybutane (DEB). This article presents the data obtained from application of the comparative CT method to the amplification of twelve apoptotic genes in human MCF10-A cells and eight genes in HUVEC cells. Further insight regarding the significance of these data can be found in "Cross-linking by epichlorohydrin and diepoxybutane correlates with cytotoxicity and leads to apoptosis in human leukemia (HL-60) cells" (Le et al...
August 2018: Data in Brief
Yuji Nishiura, Akira Matsumura, Naotake Kobayashi, Atsuyuki Shimazaki, Shingo Sakamoto, Naohisa Kitade, Yutaka Tonomura, Akira Ino, Takayuki Okuno
Novel acetyl-CoA carboxylase 2 (ACC2) selective inhibitors were identified by the conversion of the alkyne unit of A-908292 to the olefin linker. Modification of the center and left part of the lead compound 1b improved the ACC2 inhibitory activity and CYP450 inhibition profile, and afforded a highly selective ACC2 inhibitor 2e which showed in vivo efficacy in C57BL/6 mice.
June 4, 2018: Bioorganic & Medicinal Chemistry Letters
Vignesh K Rangasami, Brijesh Lohchania, Chandrashekhar Voshavar, Harikrishna R Rachamalla, Rajkumar Banerjee, Ashish Dhayani, Saravanabhavan Thangavel, Praveen K Vemula, Srujan Marepally
Intracellular delivery of nucleic acids is one of the critical steps in the transfections. Prior findings demonstrated various strategies including membrane fusion, endosomal escape for the efficient cytoplasmic delivery. In our continuing efforts to improve the nucleic acids transfections, we harnessed cell permeable properties of Tomatidine (T), a steroidal alkaloid abundantly found in green tomatoes for maximizing intracellular delivery of lipoplexes. We doped Tomatidine into liposomes of cationic lipid with amide linker (A) from our lipid library...
June 11, 2018: Biochimica et Biophysica Acta
Kazunori Yamada, Masahiko Zuka, Kiyoaki Ito, Keishi Mizuguchi, Yasushi Kakuchi, Tamehito Onoe, Yasunori Suzuki, Masakazu Yamagishi, Shozo Izui, Marie Malissen, Bernard Malissen, Mitsuhiro Kawano
BACKGROUND: The adaptor protein Linker for activation of T cell (LAT) is a key signaling hub used by the T cell antigen receptor. Mutant mice expressing loss-of-function mutations affecting LAT and including a mutation in which tyrosine 136 is replaced by a phenylalanine (LatY136F) develop lymphoproliferative disorder involving T helper type 2 effector cells capable of triggering a massive polyclonal B cell activation that leads to hypergammaglobulinemia G1 and E and to non-resolving inflammation and autoimmunity...
2018: PloS One
Ke Luo, Ki-Baek Jeong, Sang-Mook You, Da-Hee Lee, Young-Rok Kim
Herein, we report a fairly simple and environmentally friendly approach for the fabrication of starch-based magnetic polymer beads (SMPBs) with uniform shape and size through spontaneous rearrangement of short chain glucan (SCG) produced by enzymatic debranching of waxy maize starch. The paramagnetic materials, dextran-coated iron oxide nanoparticles (Dex@IONPs), were readily incorporated into the starch microstructure and rendered a superparamagnetic property to the SMPBs. The morphology and size of resulting SMPBs turned out to be modulated by Dex@IONPs in concentration dependent manner, of which Dex@IONPs was assumed to be acting as a seed inducing the epitaxial crystallization of SCG and further transforming it into homogeneous microparticles...
June 14, 2018: Journal of Agricultural and Food Chemistry
Qiang Yan, Liang Chen, Renjie Liu
Frustrated Lewis pair (FLP), as a couple of sterically encumbered Lewis acid and Lewis base, can offer latent reactivity for activating inert gas molecules. However, their use as a platform for fabricating gas-responsive materials has yet developed. Merging FLP concept and polymers, we report a new generation of CO2-responsive system, differing from the first-generation ones based on acid-base equilibrium mechanism. Two complementary Lewis acidic and basic block copolymers, installing bulky borane- and phosphine-containing blocks, were built as the macromolecular FLP...
June 14, 2018: Angewandte Chemie
Chenggong Hu, Yongfang Zhou, Chang Liu, Yan Kang
Gastric cancer (GC) is the fifth most common cancer and the third leading cause of cancer-associated mortality worldwide. In the current study, comprehensive bioinformatic analyses were performed to develop a novel scoring system for GC risk assessment based on CAP-Gly domain containing linker protein family member 4 (CLIP4) DNA methylation status. Two GC datasets with methylation sequencing information and mRNA expression profiling were downloaded from the The Cancer Genome Atlas and Gene Expression Omnibus databases...
June 6, 2018: International Journal of Oncology
Rajan Kumar Pandey, Rupal Ojha, Amit Mishra, Vijay Kumar Prajapati
The Zika virus is a rapidly spreading Aedes mosquito-borne sickness, which creates an unanticipated linkage birth deformity and neurological turmoil. This study represents the use of the combinatorial immunoinformatics approach to develop a multiepitope subunit vaccine using the structural and nonstructural proteins of the Zika virus. The designed subunit vaccine consists of cytotoxic T-lymphocyte and helper T-lymphocyte epitopes accompanied by suitable adjuvant and linkers. The presence of humoral immune response specific B-cell epitopes was also confirmed by B-cell epitope mapping among vaccine protein...
June 14, 2018: Journal of Cellular Biochemistry
Padmabati Mondal, Giovanni Granucci, Dominique Rastädter, Maurizio Persico, Irene Burghardt
The photoregulation of nucleic acids by azobenzene photoswitches has recently attracted considerable interest in the context of emerging biotechnological applications. To understand the mechanism of photoinduced isomerisation and conformational control in these complex biological environments, we employ a Quantum Mechanics/Molecular Mechanics (QM/MM) approach in conjunction with nonadiabatic Surface Hopping (SH) dynamics. Two representative RNA-azobenzene complexes are investigated, both of which contain the azobenzene chromophore covalently attached to an RNA double strand via a β-deoxyribose linker...
May 28, 2018: Chemical Science
Gulam M Rather, Siang-Yo Lin, Hongxia Lin, Whitney Banach-Petrosky, Kim M Hirshfield, Chen-Yong Lin, Michael D Johnson, Zoltan Szekely, Joseph R Bertino
The antitumor effects of a novel antibody drug conjugate (ADC) was tested against human solid tumor cell lines and against human triple negative breast cancer (TNBC) xenografts in immunosuppressed mice. The ADC targeting activated matriptase of tumor cells was synthesized by using the potent anti-tubulin toxin, monomethyl auristatin-E linked to the activated matriptase-specific monoclonal antibody (M69) via a lysosomal protease-cleavable dipeptide linker. This ADC was found to be cytotoxic against multiple activated matriptase-positive epithelial carcinoma cell lines in vitro and markedly inhibited growth of triple negative breast cancer xenografts and a primary human TNBC (PDX) in vivo ...
May 25, 2018: Oncotarget
Vandana Solanki, Vishvanath Tiwari
The emergence of drug-resistant Acinetobacter baumannii is the global health problem associated with high mortality and morbidity. Therefore it is high time to find a suitable therapeutics for this pathogen. In the present study, subtractive proteomics along with reverse vaccinology approaches were used to predict suitable therapeutics against A. baumannii. Using subtractive proteomics, we have identified promiscuous antigenic membrane proteins that contain the virulence factors, resistance factors and essentiality factor for this pathogenic bacteria...
June 13, 2018: Scientific Reports
Xing Li, Qiang Gao, Juefan Wang, Yifeng Chen, Zhi-Hui Chen, Hai-Sen Xu, Wei Tang, Kai Leng, Guo-Hong Ning, Jishan Wu, Qing-Hua Xu, Su Ying Quek, Yixin Lu, Kian Ping Loh
Most two-dimensional (2D) covalent organic frameworks (COFs) are non-fluorescent in the solid state even when they are constructed from emissive building blocks. The fluorescence quenching is usually attributed to non-irradiative rotation-related or π-π stacking-caused thermal energy dissipation process. Currently there is a lack of guiding principle on how to design fluorescent, solid-state material made of COF. Herein, we demonstrate that the eclipsed stacking structure of 2D COFs can be used to turn on, and tune, the solid-state photoluminescence from non-emissive building blocks by the restriction of intramolecular bond rotation via intralayer and interlayer hydrogen bonds among highly organized layers in the eclipse-stacked COFs...
June 13, 2018: Nature Communications
Jiaqi Yuan, Chunhua Yuan, Mouzhe Xie, Lei Yu, Lei Bruschweiler-Li, Rafael Bruschweiler
The Na+/Ca2+ exchanger (NCX) is a ubiquitous single-chain membrane protein that plays a major role in regulating the intracellular Ca2+ homeostasis by the counter transport of Na+ and Ca2+ across the cell membrane. Other than its prokaryotic counterpart, which contains only the transmembrane domain and is self-sufficient as an active ion transporter, the eukaryotic NCX protein possesses in addition a large intracellular loop that senses intracellular calcium signals and controls the activation of ion transport across the membrane...
June 13, 2018: Biochemistry
Chen Wei, Zhenwei Yuan, Jinrong Zheng, Habtamu Kassaye, Lijuan Gui, Fei Wang, Hao Wan, Yue Xu, Qing He, Murat Er, Yi Ma, Haiyan Chen
Methionine (Met), one of the essential amino acids, of which the transport system L is over-expressed in various tumor cells. In this study, a near-infrared fluorescent dye (IR-780) and methionine were conjugated through a piperazin-polyamines linker to form Cy-Met. The successful synthesis of Cy-Met was validated by optical characterization, NMR and MS spectra. The absorption peak of Cy-Met was at 680 nm and fluorescence peak was at 790 nm. Cytotoxicity assay and cell imaging studies indicated that Cy-Met had good biocompatibility and specific affinity to tumor cells...
June 13, 2018: Molecular Pharmaceutics
Matthias Benoit, Lauriane Simon, Sophie Desset, Céline Duc, Sylviane Cotterell, Axel Poulet, Samuel Le Goff, Christophe Tatout, Aline V Probst
Developmental phase transitions are often characterized by changes in the chromatin landscape and heterochromatin reorganization. In Arabidopsis, clustering of repetitive heterochromatic loci into so-called chromocenters is an important determinant of chromosome organization in nuclear space. Here, we investigated the molecular mechanisms involved in chromocenter formation during the switch from a heterotrophic to a photosynthetically competent state during early seedling development. We characterized the spatial organization and chromatin features at centromeric and pericentromeric repeats and identified mutant contexts with impaired chromocenter formation...
June 13, 2018: New Phytologist
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