分类: 生物学 >> 生物物理学 提交时间: 2016-05-11
摘要: Enterovirus 71 (EV71), a primary pathogen of hand, foot, and mouth disease (HFMD), affects primarily infants and children. Currently, there are no effective drugs against HFMD. EV71 3C protease performs multiple tasks in the viral replication, which makes it an ideal antiviral target. We synthesized a small set of fluorogenic model peptides derived from cleavage sites of EV71 polyprotein and examined their efficiencies of cleavage by EV71 3C protease. The novel peptide P08 [(2-(N-methylamino)benzoyl) (NMA)-IEALFQGPPK(DNP)FR] was determined to be the most efficiently cleaved by EV71 3C protease, with a kinetic constant k(cat)/K-m of 11.8 +/- 0.82mM(-1) min(-1). Compared with literature reports, P08 gave significant improvement in the signal/background ratio, which makes it an attractive substrate for assay development. A Molecular dynamics simulation study elaborated the interactions between substrate P08 and EV71 3C protease. Arg39, which is located at the bottom of the S2 pocket of EV71 3C protease, may participate in the proteolysis process of substrates. With an aim to evaluate EV71 3C protease inhibitors, a reliable and robust biochemical assay with a Z' factor of 0.87 +/- 0.05 was developed. A novel compound (compound 3) (50% inhibitory concentration [IC50] = 1.89 +/- 0.25 mu M) was discovered using this assay, which effectively suppressed the proliferation of EV 71 (strain Fuyang) in rhabdomyosarcoma (RD) cells with a highly selective index (50% effective concentration [EC50] = 4.54 +/- 0.51 mu M; 50% cytotoxic concentration [CC50] > 100 mu M). This fast and efficient assay for lead discovery and optimization provides an ideal platform for anti-EV71 drug development targeting 3C protease.
分类: 生物学 >> 生物物理学 提交时间: 2016-05-11
摘要: Cyanohydrin derivatives as enterovirus 71 (EV71) 3C protease (3C(pro)) inhibitors have been synthesized and assayed for their biochemical and antiviral activities. Compared with the reported inhibitors, cyanohydrins (1S,2S,2'S,5S)-16 and (1R,2S,2'S,5S)-16 exhibited significantly improved activity and attractive selectivity profiles against other proteases, which were a result of the specific interactions between the cyanohydrin moiety and the catalytic site of 3C(pro). Cyanohydrin as an anchoring group with high selectivity and excellent inhibitory activity represents a useful choice for cysteine protease inhibitors.
提交时间: 2017-05-02
摘要: Crystalline silicon thin film [c-Si TF] solar cells with an active layer thickness of a few micrometers may provide a viable pathway for further sustainable development of photovoltaic technology, because of its potentials in cost reduction and high effic
提交时间: 2017-05-02
分类: 物理学 >> 普通物理:统计和量子力学,量子信息等 提交时间: 2017-05-02
摘要: In this study, an artificial synapse with a sandwich structure of Ta/ethyl viologen diperchlorate [EV(ClO4)2]/triphenylamine-based polyimide (TPA-PI)/Pt is fabricated directly on a flexible PET substrate and exhibits distinctive history-dependent memristive behaviour, which meets the basic requirements for synapse emulation. Essential synaptic plasticity (including long-term plasticity and short-term plasticity) and some memory and learning behaviours of human beings (including the conversion from short-term memory to long-term memory and the ‘‘learning–forgetting–relearning’’) have been demonstrated in our device. More importantly, the device still exhibits the synaptic performance when the surface strain of the device reaches 0.64% (or, the bending radius reaches 10 mm). Moreover, the device was able to endure 100 bending cycles. Our findings strongly demonstrate that the organic artificial synapse is not only promising for constructing a neuromorphic information storage and processing system, but is also interesting for the realization of wearable neuromorphic computing systems