The synthesis and anti-influenza activity study of Diels-Alder adducts of 3-N-substituted derivatives of (−)-cytisine with N-substituted maleimides are described. Synthesized compounds were studied for antiviral activity against influenza virus A/California/07/09 (H1N1)pdm09 in MDCK. The values of CC50, IC50 and selectivity indexes (SI) of obtained derivatives were determined. It was shown that anti-influenza activity of ‘α-endo’ adducts is higher (SI of three samples is 79 and higher) than activity of ‘β-endo’ adducts. By means of ‘time-of-addition’ experiment it was established that the leading compound (3aS,4R,8S,12R,12aR,12bS)-10-benzyl-2-phenyloctahydro-1H-4,12a-etheno-8,12-methanopyrrolo[3′,4':3,4]pyrido[1,2-a][1,5]diazocine-1,3,5(4H)-trione (16a) demonstrates anti-influenza activity at the middle and late stages of the virus life cycle. The possibility of interaction of synthesized derivatives with the active sites of the PAN and PB2 was estimated via in silico approach. The difference in the locations of ‘α-endo’ and ‘β-endo’ adducts in PB2 active site (5JUN) is offered as an explanation of the dependence of their virus-inhibiting properties on stereochemistry. 相似文献
The affinity inhibitor of fusion peptide of influenza A virus has been studied using a combination of high-performance affinity chromatography (HPAC) and combinatorial peptide libraries. Fusion peptide (FP) (1-11) of influenza A virus was used as the affinity ligand and immobilized onto the poly(glycidyl methacrylate) (PGMA) beads. Positional scanning peptide libraries based on antisense peptide strategy and extended peptide libraries were designed and synthesized. The screening was carried out at acidic pH (5.5) in order to imitate the environment of virus fusion. A hendecapeptide FHRKKGRGKHK was identified to have a strong affinity to the FP (1-11). The dissociation constant of the complex of the hendecapeptide and the FP (1-11) is 3.10 x 10(-6) mol l(-1) in a physiological buffer condition. The polypeptide has a fairly inhibitory effect on three different strains of influenza A virus H1N1 subtype. 相似文献
The hemagglutinin (HA) protein of the influenza virus binds to the host cell receptor in the early stage of viral infection. A change in binding specificity from avian 2-3 to human 2-6 receptor is essential for optimal human-to-human transmission and pandemics. Therefore, it is important to reveal the key factors governing the binding affinity of HA-receptor complex at the molecular level for the understanding and prediction of influenza pandemics. In this work, on the basis of ab initio fragment molecular orbital (FMO) method, we have carried out the interaction energy analysis of HA-receptor complexes to quantitatively elucidate the binding specificity of HAs to avian and human receptors. To discuss the binding property of influenza HA comprehensively, a number of HAs from human H1, swine H1, avian H3 and avian H5 viruses were analyzed. We performed detailed investigations about the interaction patterns of complexes of various HAs and receptor analogues, and revealed that intra-molecular interactions between conserved residues in HA play an important role for HA-receptor binding. These results may provide a hint to understand the role of conserved acidic residues at the receptor binding site which are destabilized by the electrostatic repulsion with sialic acid. The calculated binding energies and interaction patterns between receptor and HAs are consistent with the binding specificities of each HA and thus explain the receptor binding mechanism. The calculated results in the present analysis have provided a number of viewpoints regarding the models for the HA-receptor binding specificity associated with mutated residues. Examples include the role of Glu190 and Gln226 for the binding specificity of H5 HA. Since H5 HA has not yet been adapted to human receptor and the mechanism of the specificity change is unknown, this result is helpful for the prediction of the change in receptor specificity associated with forthcoming possible pandemics. 相似文献
Influenza remains a health problem to humans. Peramivir is a FDA approved anti-influenza drug targeting the virus neuraminidase. The (3 + 2) cycloaddition reaction of 2-ethylbutanenitrile oxide with the cyclopentene dipolarophile derived from Vince lactam is a key step in the conventional synthesis of peramivir. Our study showed that conducting the (3 + 2) cycloaddition reactions with either aliphatic or aromatic nitrile oxide in hexane solution provided high percentage of the desired regioisomer, and the N-substituent having electron-withdrawing property is also beneficial to the regioselectivity. This study also demonstrated an alternative synthetic pathway of (−)-peramivir and the analog having a phenyl group in place of the 3-pentyl moiety. 相似文献
A DNA biosensor for the detection of specific oligonucleotide sequences of Avian Influenza Virus type H5N1 has been proposed. The NH2‐ssDNA probe was deposited onto a gold electrode surface to form an amide bond between the carboxyl group of thioacid and the amino group from ssDNA probe. The signals generated as a result of hybridization were registered in square wave voltammetry and electrochemical impedance spectroscopy in the presence of [Fe(CN)6]3?/4? as a redox marker. The genosensor is capable to determine 20‐mer and 180‐bp (PCR products) oligonucleotides complementary sequences with detection limit in the fM range. The genosensor displays good selectivity and sensitivity. The 20‐mer as well as 180‐bp oligonucleotides without a complementary sequence generate very low signal. 相似文献
Sialic acids are essential components of host‐cell surface receptors for infection of influenza virus. To investigate the specific receptor structures recognized by various influenza A viruses, a series of lacto‐ and neolacto‐series ganglioside analogs containing N‐glycolylneuraminic acid (Neu5Gc) have been synthesized. The pentasaccharide structures of Neu5Gc‐α‐(2→3)/(2→6)‐lactotetraose (IV3(6)Neu5GcLcOse) and Neu5Gc‐α‐(2→3)/(2→6)‐neolactotetraose (IV3(6)Neu5GcnLcOse) were constructed by glycosylation of the suitably protected trisaccharide acceptors (2A and 2B) with the Neu5Gc‐α‐(2→3)/(2→6)‐Gal trichloroacetimidate donors (1 and 21), respectively. Transformation of the 2‐(trimethylsilyl)ethyl group at the reducing end in 4, 11, 23, and 30 into the trichloroacetimidate group gave a series of Neu5Gc‐α‐(2→3)/(2→6)‐lacto‐ and neolactotetraose donors (7, 13, 26, and 33), which were coupled with 2‐(tetradecyl)hexadecanol (8), to give the corresponding glycolipids (9, 14, 27, and 34). Finally, the complete removal of the O‐acyl groups and saponification of the methyl ester group gave the desired ganglioside analogs (10, 15, 28, and 35). 相似文献
This article reviews quantitative methods to estimate the basic reproduction number of pandemic influenza, a key threshold quantity to help determine the intensity of interventions required to control the disease. Although it is difficult to assess the transmission potential of a probable future pandemic, historical epidemiologic data is readily available from previous pandemics, and as a reference quantity for future pandemic planning, mathematical and statistical analyses of historical data are crucial. In particular, because many historical records tend to document only the temporal distribution of cases or deaths (i.e. epidemic curve), our review focuses on methods to maximize the utility of time-evolution data and to clarify the detailed mechanisms of the spread of influenza.
First, we highlight structured epidemic models and their parameter estimation method which can quantify the detailed disease dynamics including those we cannot observe directly. Duration-structured epidemic systems are subsequently presented, offering firm understanding of the definition of the basic and effective reproduction numbers. When the initial growth phase of an epidemic is investigated, the distribution of the generation time is key statistical information to appropriately estimate the transmission potential using the intrinsic growth rate. Applications of stochastic processes are also highlighted to estimate the transmission potential using similar data. Critically important characteristics of influenza data are subsequently summarized, followed by our conclusions to suggest potential future methodological improvements. 相似文献