- Immobilization of liposomes and vesicles on patterned surfaces by a peptide coiled-coil binding motif
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Patchy surfaces: An azide-terminated self-assembled monolayer was patterned with the peptide sequence (EIAALEK)3 by using microcontact printing. This sequence forms stable coiled-coil heterodimers with the complementary peptide (KIAALKE)3
- Voskuhl, Jens,Wendeln, Christian,Versluis, Frank,Fritz, Eva-Corinna,Roling, Oliver,Zope, Harshal,Schulz, Christian,Rinnen, Stefan,Arlinghaus, Heinrich F.,Ravoo, Bart Jan,Kros, Alexander
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Read Online
- Synthesis of polyanionic c5-modified 2′-deoxyuridine and 2′-deoxycytidine-5′-triphosphates and their properties as substrates for dna polymerases
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Modified 2′-deoxyribonucleotide triphosphates (dNTPs) have widespread applications in both existing and emerging biomolecular technologies. For such applications it is an essential requirement that the modified dNTPs be substrates for DNA polymerases. To date very few examples of C5-modified dNTPs bearing negatively charged functionality have been described, despite the fact that such nucleotides might potentially be valuable in diagnostic applications using Si-nanowire-based detection systems. Herein we have synthesised C5-modified dUTP and dCTP nucleotides each of which are labelled with an dianionic reporter group. The reporter group is tethered to the nucleobase via a polyethylene glycol (PEG)-based linkers of varying length. The substrate properties of these modified dNTPs with a variety of DNA polymerases have been investigated to study the effects of varying the length and mode of attachment of the PEG linker to the nucleobase. In general, nucleotides containing the PEG linker tethered to the nucleobase via an amide rather than an ether linkage proved to be the best substrates, whilst nucleotides containing PEG linkers from PEG6 to PEG24 could all be incorporated by one or more DNA polymerase. The polymerases most able to incorporate these modified nucleotides included Klentaq, Vent(exo-) and therminator, with incorporation by Klenow(exo-) generally being very poor.
- Allen, Esther,Dutson, Claire,Hedley, Joseph H.,Murton, Heather E.,Thompson, Mark J.,Williams, David M.
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Read Online
- Optical Manipulation of Subcellular Protein Translocation Using a Photoactivatable Covalent Labeling System
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The photoactivatable chemically induced dimerization (photo-CID) technique for tag-fused proteins is one of the most promising methods for regulating subcellular protein translocations and protein–protein interactions. However, light-induced covalent protein dimerization in living cells has yet to be established, despite its various advantages. Herein, we developed a photoactivatable covalent protein-labeling technology by applying a caged ligand to the BL-tag system, a covalent protein labeling system that uses mutant β-lactamase. We further developed CBHD, a caged protein dimerizer, using caged BL-tag and HaloTag ligands, and achieved light-induced protein translocation from the cytoplasm to subcellular regions. In addition, this covalent photo-CID system enabled quick protein translocation to a laser-illuminated microregion. These results indicate that the covalent photo-CID system will expand the scope of CID applications in the optical manipulation of cellular functions.
- Kowada, Toshiyuki,Arai, Keisuke,Yoshimura, Akimasa,Matsui, Toshitaka,Kikuchi, Kazuya,Mizukami, Shin
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supporting information
p. 11378 - 11383
(2021/04/09)
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- TARGETED BIFUNCTIONAL DEGRADERS
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The present invention provides, in one aspect, bifunctional compounds that can be used to promote or enhance degradation of certain circulating proteins. In another aspect, the present invention provides bifunctional compounds that can be used to promote or enhance degradation of certain autoantibodies. In certain embodiments, treatment or management of a disease and/or disorder requires degradation, removal, or reduction in concentration of the circulating protein or the autoantibody in the subject. Thus, in certain embodiments, administration of a compound of the invention to the subject removes or reduces the circulation concentration of the circulating protein or the autoantibody, thus treating, ameliorating, or preventing the disease and/or disorder. In certain embodiments, the circulating protein is TNF.
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- F-labeled PSMA targeted diagnosis and treatment integrated small-molecular drug conjugate, preparation method and application of F-labeled PSMA targeted diagnosis and treatment integrated small-molecular drug conjugate
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The invention relates to a tumor targeted diagnosis and treatment integrated drug compound, in particular to an F-labeled PSMA targeted diagnosis and treatment integrated small molecular drug conjugate, a preparation method and an application of th
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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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- 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 100; 107
(2019/11/12)
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- Bladder Cancer Photodynamic Therapeutic Agents with Off-On Magnetic Resonance Imaging Enhancement
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Provided herein are porphyrinato-lanthanide complexes useful as theranostic agents and methods of preparation and use thereof. The porphyrinato-lanthanide complexes are useful in the treatment and imaging of cancer.
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- Irreversible Cysteine-Selective Protein Labeling Employing Modular Electrophilic Tetrafluoroethylation Reagents
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Fluoroalkylation reagents based on hypervalent iodine are widely used to transfer fluoroalkyl moieties to various nucleophiles. However, the transferred groups have so far been limited to simple structural motifs. We herein report a reagent featuring a secondary amine that can be converted to amide, sulfonamide, and tertiary amine derivatives in one step. The resulting reagents bear manifold functional groups, many of which would not be compatible with the original synthetic pathway. Exploiting this structural versatility and the known high reactivity toward thiols, the new-generation reagents were used in bioconjugation with an artificial retro-aldolase, containing an exposed cysteine and a reactive catalytic lysine. Whereas commercial reagents based on maleimide and iodoacetamide labeled both sites, the iodanes exclusively modified the cysteine residue. The study thus demonstrates that modular fluoroalkylation reagents can be used as tools for cysteine-selective bioconjugation.
- Václavík, Ji?í,Zschoche, Reinhard,Klimánková, Iveta,Matou?ek, Václav,Beier, Petr,Hilvert, Donald,Togni, Antonio
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supporting information
p. 6490 - 6494
(2017/05/15)
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- NANOPARTICLES FOR DIAGNOSIS AND DRUG DELIVERY
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The present invention relatesto a nanoparticle having a size comprised from 2 to 300 nm comprising: (i) a core comprising on its surface a noble metal selected from gold, silver or platinum, and (ii) an optionally positively charged amphiphilic linker comprising a hydrophobic C1-C20 alkyl thiolate moiety and a hydrophilic moietywhich is optionally hydrophilic positively charged. The invention also provides nanovectors comprising the nanoparticles of the invention and a compound of interest,such as a pharmaceutically active agent, in particular an anti-tumoral agent. Also provided are nanoparticles and nanovectors as defined above for diagnosis or for the prevention and/or treatment of a disease, in particular cancer.
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Page/Page column 42; 43
(2017/04/11)
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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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p. 17397 - 17404
(2017/12/15)
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- Multivalency Increases the Binding Strength of RGD Peptidomimetic-Paclitaxel Conjugates to Integrin αVβ3
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This work reports the synthesis of three multimeric RGD peptidomimetic-paclitaxel conjugates featuring a number of αVβ3 integrin ligands ranging from 2 to 4. These constructs were assembled by conjugation of the integrin αV/sub
- Raposo Moreira Dias, André,Pina, Arianna,Dal Corso, Alberto,Arosio, Daniela,Belvisi, Laura,Pignataro, Luca,Caruso, Michele,Gennari, Cesare
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p. 14410 - 14415
(2017/09/13)
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- Towards potential nanoparticle contrast agents: Synthesis of new functionalized PEG bisphosphonates
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The use of nanotechnologies for biomedical applications took a real development during these last years. To allow an effective targeting for biomedical imaging applications, the adsorption of plasmatic proteins on the surface of nanoparticles must be prevented to reduce the hepatic capture and increase the plasmatic time life. In biologic media, metal oxide nanoparticles are not stable and must be coated by biocompatible organic ligands. The use of phosphonate ligands to modify the nanoparticle surface drew a lot of attention in the last years for the design of highly functional hybrid materials. Here, we report a methodology to synthesize bisphosphonates having functionalized PEG side chains with different lengths. The key step is a procedure developed in our laboratory to introduce the bisphosphonate from acyl chloride and tris(trimethylsilyl)phosphite in one step.
- Kachbi-Khelfallah, Souad,Monteil, Maelle,Cortes-Clerget, Margery,Migianu-Griffoni, Evelyne,Pirat, Jean-Luc,Gager, Olivier,Deschamp, Julia,Lecouvey, Marc
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supporting information
p. 1366 - 1370
(2016/08/02)
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- METHOD FOR CELL MEMBRANE PERMEATION FOR COMPOUND
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The present invention discloses a cell-penetrating method for compounds, comprising the following steps of: (1) preparing raw materials, i.e., the compounds and DNA or RNA; (2) linking: linking the compounds to the DNA or RNA to obtain a molecular conjuga
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- COMPOUND ADMINISTRATION PRECURSOR AND MEDICAMENT CARRIER PREPARATION
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The present invention provides a compound drug-delivery precursor for membrane permeation, and a drug carrier preparation based on this precursor. The compound drug-delivery precursor and the drug carrier preparation of the present invention may effective
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- TARGETED DRUG DELIVERY THROUGH AFFINITY BASED LINKERS
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The current invention discloses targeted drug delivery conjugates comprising a targeting moiety linked to a drug via a molecule having an affinity for the targeting moiety. Typically, the conjugate comprises a targeting ligand and a molecule of interest, e.g., a therapeutic agent. The targeting ligand and the molecule of interest are linked to each other via an affinity ligand. The affinity ligand is further covalently or non-covalently linked to a drug or therapeutic agent. The drug can be modified to make it more soluble and so that it cleaves from the linking molecule at the target site.
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Paragraph 00293
(2015/12/08)
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- Self-assembled multivalent RGD-peptide arrays-morphological control and integrin binding
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We report the synthesis of four different RGD peptide derivatives which spontaneously self-assemble into nanoscale architectures. Depending on the information programmed into the molecular-scale building blocks by organic synthesis, these compounds assemble into different nanoscale morphologies. This process can be fully understood using multiscale modelling which provides predictive insight into subtle differences, such as whether the compounds form spherical micelles, rod-like cylinders or tubular assemblies, and predicts experimentally observed critical aggregation concentrations (CACs). We then probe the multivalent binding of these assemblies to integrin proteins and demonstrate that the spherical micellar assemblies perform well in our solution-phase integrin binding assay as a consequence of self-assembled multivalency, with the CAC switching-on the binding. Conversely, the cylindrical assemblies do not work in this assay. As such, the nanoscale morphology controls the apparent ability to perform as a self-assembled multivalent ligand array. The Royal Society of Chemistry 2013.
- Welsh, Daniel J.,Posocco, Paola,Pricl, Sabrina,Smith, David K.
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p. 3177 - 3186
(2013/06/05)
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- Protein-inorganic array construction: Design and synthesis of the building blocks
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Herein we describe the design and synthesis of the first series of di-functional ligands for the directed construction of inorganic-protein frameworks. The synthesized ligands are composed of a metal-ion binding moiety (terpyridine-based) conjugated to an epoxysuccinyl peptide, known to covalently bind active cysteine proteases through the active-site cysteine. We explore and optimize two different conjugation chemistries between the di-functionalized metal-ion ligand and the epoxysuccinyl-containing peptide moiety: peptide-bond formation (with limited success) and Cu'-catalysed click chemistry (with good results). Further, the complexation of the synthesized ligands with Fe" and NiII" ions is investigated: the di-functional ligands are confirmed to behave similarly to the parent terpyridine. As designed, the peptidic moiety does not interfere with the complexation reaction, in spite of the presence of two triazole rings that result from the click reaction. ES-MS together with NMR and UV/Vis stud-ies establish the structure, the stoichiometry of the complexation reactions, as well as the conditions under which chemically sensitive peptide-containing polypyridine ligands can undergo the self-assembly process. These results establish the versatility of our approach and open the way to the synthesis of di-functional ligands containing more elaborated polypyridine ligands as well as affinity labels for different enzyme families. As such, this paper is the first step towards the construction of robust supramolecular species that cover a size-regime and organization level previously unexplored.
- Bogdan, Niculina D.,Matache, Mihaela,Meier, Veronika M.,Dobrotae, Cristian,Dumitru, Ioana,Roiban, Gheorghe D.,Funeriu, Daniel P.
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experimental part
p. 2170 - 2180
(2010/07/05)
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- LINKER COMPOUND, LIGAND COMPLEX AND PROCESS FOR PRODUCING THEM
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The present invention provides a novel linker compound which minimizes any nonspecific hydrophobic interactions and is capable of easily adjusting the length to a disulfide group subjected to metal bond to thereby enable effective formation of a metal-sulfur bond; novel ligand conjugate and ligand carrier, and a process for producing them. The linker compound is of a structure represented by the following general formula (1) where a, b, d, e are independently an integer of 0 to 6. X has a structure serving as a multi-branched structure moiety including three or more hydrocarbon derivative chains, wherein the hydrocarbon derivative chains each include an aromatic amino group at an end thereof, and may or may not include a carbon-nitrogen bond in a main chain thereof. The ligand conjugate includes the linker compound having a sugar molecule introduced therein.
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Page/Page column 27
(2010/11/25)
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- SUGAR CHAIN LIGAND COMPOSITE AND METHOD OF ANALYZING PROTEIN WITH THE LIGAND COMPOSITE
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A novel ligand conjugate which is effectively utilizable for analyzing a function of a protein; a ligand-supporting object; and a method of analyzing a protein. The ligand conjugate has a structure which comprises: a linker compound having a structure represented by the following General Formula (1): (wherein n and p each is an integer of 0 to 6) in which X is a structure comprising one, two, or three hydrocarbon derivative chains which have an aromatic amino group at the end and may have a carbon-nitrogen bond in the main chain, Y is a hydro-carbon structure containing one or more sulfur atoms, and Z is a straight-chain structure comprising a carbon-carbon bond or carbon-oxygen bond; and a sugar which has a reducing end and is bonded to the linker compound through the aromatic amino group.
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Page/Page column 32
(2010/11/24)
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- Polyamide oligomers
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The present invention relates to new polyamide oligomers. These oligomers can be conjugated to lipids, nucleic acids, peptides, proteins, etc. The oligomer-lipid conjugates can be used to form liposomes, virusomes, micelles, etc., optionally containing drugs or biological agents. The polyamide oligomers are heterobifunctional allowing the attachment of other suitable ligand compounds (e.g., a targeting moiety). In addition, methods of use for the liposomes, virusomes, micelles, etc., are provided.
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