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排序方式: 共有339条查询结果,搜索用时 15 毫秒
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Dr. Hui Qiu Richard Caldwell Dr. Lesley Liu-Bujalski Dr. Andreas Goutopoulos Reinaldo Jones Justin Potnick Dr. Brian Sherer Dr. Andrew Bender Dr. Roland Grenningloh Dr. Daigen Xu Dr. Anna Gardberg Dr. Igor Mochalkin Dr. Theresa Johnson Dr. Ariele Viacava Follis Jared Head Dr. Federica Morandi 《ChemMedChem》2019,14(2):217-223
Bruton's tyrosine kinase (Btk) is an attractive target for the treatment of a wide array of B-cell malignancies and autoimmune diseases. Small-molecule covalent irreversible Btk inhibitors targeting Cys481 have been developed for the treatment of such diseases. In clinical trials, probe molecules are required in occupancy studies to measure the level of engagement of the protein by these covalent irreversible inhibitors. The result of this pharmacodynamic (PD) activity provides guidance for appropriate dosage selection to optimize inhibition of the drug target and correlation of target inhibition with disease treatment efficacy. This information is crucial for successful evaluation of drug candidates in clinical trials. Based on the pyridine carboxamide scaffold of a novel solvent-accessible pocket (SAP) series of covalent irreversible Btk inhibitors, we successfully developed a potent and selective affinity-based biotinylated probe 12 (2-[(4-{4-[5-(1-{5-[(3aS,4S,6aR)-2-oxo-hexahydro-1H-thieno[3,4-d]imidazol-4-yl]pentanamido}-3,6,9,12-tetraoxapentadecan-15-amido)pentanoyl]piperazine-1-carbonyl}phenyl)amino]-6-[1-(prop-2-enoyl)piperidin-4-yl]pyridine-3-carboxamide). Compound 12 has been used in Btk occupancy assays for preclinical studies to determine the therapeutic efficacy of Btk inhibition in two mouse lupus models driven by TLR7 activation and type I interferon. 相似文献
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Corey Nelson Tyler Mrozowich Darren L. Gemmill Sean M. Park Trushar R. Patel 《International journal of molecular sciences》2021,22(1)
Flavivirus genus includes many deadly viruses such as the Japanese encephalitis virus (JEV) and Zika virus (ZIKV). The 5′ terminal regions (TR) of flaviviruses interact with human proteins and such interactions are critical for viral replication. One of the human proteins identified to interact with the 5′ TR of JEV is the DEAD-box helicase, DDX3X. In this study, we in vitro transcribed the 5′ TR of JEV and demonstrated its direct interaction with recombinant DDX3X (Kd of 1.66 ± 0.21 µM) using microscale thermophoresis (MST). Due to the proposed structural similarities of 5′ and 3′ TRs of flaviviruses, we investigated if the ZIKV 5′ TR could also interact with human DDX3X. Our MST studies suggested that DDX3X recognizes ZIKV 5′ TR with a Kd of 7.05 ± 0.75 µM. Next, we performed helicase assays that suggested that the binding of DDX3X leads to the unwinding of JEV and ZIKV 5′ TRs. Overall, our data indicate, for the first time, that DDX3X can directly bind and unwind in vitro transcribed flaviviral TRs. In summary, our work indicates that DDX3X could be further explored as a therapeutic target to inhibit Flaviviral replication 相似文献
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Siriluk Ratanabunyong Dr. Niran Aeksiri Dr. Saeko Yanaka Dr. Maho Yagi-Utsumi Dr. Koichi Kato Dr. Kiattawee Choowongkomon Dr. Supa Hannongbua 《Chembiochem : a European journal of chemical biology》2021,22(5):915-923
HIV-1 RT is a necessary enzyme for retroviral replication, which is the main target for antiviral therapy against AIDS. Effective anti-HIV-1 RT drugs are divided into two groups; nucleoside inhibitors (NRTI) and non-nucleoside inhibitors (NNRTI), which inhibit DNA polymerase. In this study, new DNA aptamers were isolated as anti-HIV-1 RT inhibitors. The selected DNA aptamer (WT62) presented with high affinity and inhibition against wild-type (WT) HIV-1 RT and gave a KD value of 75.10±0.29 nM and an IC50 value of 84.81±8.54 nM. Moreover, WT62 decreased the DNA polymerase function of K103 N/Y181 C double mutant (KY) HIV-1 RT by around 80 %. Furthermore, the ITC results showed that this aptamer has small binding enthalpies with both WT and KY HIV-1 RTs through which the complex might form a hydrophobic interaction or noncovalent bonding. The NMR result also suggested that the WT62 aptamer could bind with both WT and KY mutant HIV-1 RTs at the connection domain. 相似文献
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The effects of lanthanum (Ⅲ) on the bone resorbing activity of rabbit mature osteoclasts (OCs) in the presence of osteoblasts (OBs) were studied in vitro by measuring the number and area of absorption pits. La(Ⅲ) at concentrations ranging from 1.00×10-5 to 1.00×10-8 mol·L-1 show no effect on mature OC number (P>0.05). In the OC-OB co-culture systems without La(Ⅲ), osteoblasts alone did not influence the pit number and area whether the two kinds of cells were in contact or not (P>0.05). Under the OC-OB not-in-contact condition, the effect of La(Ⅲ) on the bone-resorbing activity of OCs was similar to that of La(Ⅲ) in the absence of OBs (P>0.05). However, while OCs were in direct contact with OBs, the inhibitory effects of La(Ⅲ) on OCs' bone-resorbing activity decreased at the concentrations of 1.00×10-5, 1.00×10-6 and 1.00×10-7 mol·L-1, and the promotion effects increased at 1.00×10-8 mol·L-1 (P<0.05). The results suggest that direct cell-cell contact between OC and OB be essential for OBs to play their role in regulating the response of OCs to La(Ⅲ). 相似文献
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Effects of Lanthanum on Formation and Bone-Resorbing Activity of Osteoclast-Like Cells 总被引:3,自引:0,他引:3
The effect of La3 on formation of osteoclast-like cells in rabbit bone marrow cells induced by 1,25-dihydroxyvitamin D3 and their bone-resorbing activity was evaluated by counting the number of tartrate resistant-acid phosphatase-positive [TRAP( )] multi-nucleated cells and measuring the number and surface area of bone resorption pits with photomicrography and image analysis. The formation and morphological characteristics of osteoclast-like cells and bone resorption pits were observed under a phase contrast inverted microscope. La3 promotes the formation of osteoclast-like cells at the concentration of 1.00×10-8mol·L-1 compared with the control group(P<0.01), whereas no significant change in cell number is observed at higher concentrations(1.00×10-5, 1.00×10-6 and 1.00×10-7 mol·L-1)(P>0.05). La3 at the concentration of 1.00×10-8mol·L-1 also increases the number and surface area of the resorption pits(P<0.01), but inhibits the bone-resorbing activity dose-dependently(P<0.01)at higher concentrations(1.00×10-5, 1.00×10-6 and 1.00×10-7 mol·L-1). These findings suggest that La3 may promote or inhibit the formation and bone-resorbing activity of osteoclast-like cells depending on its concentration. 相似文献
8.
Grimandi G Soueidan A Anjrini AA Badran Z Pilet P Daculsi G Faucheux C Bouler JM Guicheux J 《Microscopy research and technique》2006,69(8):606-612
The increased generation and up-regulated activity of bone resorbing cells (osteoclasts) play a part in the impairment of bone remodeling in many bone diseases. Numerous drugs (bisphosphonates, calcitonin, selective estrogen receptor modulators) have been proposed to inhibit this increased osteoclastic activity. In this report, we describe a pit resorption assay quantified by scanning electron microscopy coupled with image analysis. Total rabbit bone cells with large numbers of osteoclasts were cultured on dentin slices. The whole surface of the dentin slice was scanned and both the number of resorption pits and the total resorbed surface area were measured. Resorption pits appeared at 48 h and increased gradually up to 96 h. Despite the observation of a strong correlation between the total resorption area and the number of pits, we suggest that area measurement is the most relevant marker for osteoclastic activity. Osteotropic factors stimulating or inhibiting osteoclastic activity were used to test the variations in resorption activity as measured with our method. This reproducible and sensitive quantitative method is a valuable tool for screening for osteoclastic inhibitors and, more generally, for investigating bone modulators. 相似文献
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《Food Control》2015
Immunochromatographic assays (ICAs) are considered as a suitable diagnostic tool for the detection of mycotoxins. Mycotoxins and especially, ochratoxin A are analytes with more demanding sensitivity requirements. To enhance the sensitivity of current immunochromatographic assays for ochratoxin A (OTA), a novel sensitive ICA was developed in this study. In the assay, microspheres enclosing fluorescent europium (III) [Eu(III)] nanoparticles (EuNPs) were used as a label for OTA monoclonal antibody (OTA-mAb) conjugation. Accordingly, assay was called time-resolved fluorescent immunochromatographic assay (TRFICA). The test strip was composed of three parts: a sample pad, nitrocellulose membrane and an absorbent pad. As for detection, a proper concentration of conjugated microspheres was pipetted into the microtube and sample extract was added to it. Then the strip was inserted into the tube and the fluid flow along the strip. The TRFICA results were obtained in 8 min and read by a portable TRFICA strip reader. The established method allows quantitative determination of OTA with limit of detection as low as 1.0 μg kg−1 in the samples. For validation, spiked samples including wheat, maize, soybean and rice were respectively assayed by TRFICA and a standard high performance liquid chromatography equipped with a fluorescence detector (HPLC-FLD), and good agreement of results was obtained between two methods. 相似文献