Synthesis and biological evaluation of 6-nitro-1,2,4-triazoloazines containing polyphenol fragments possessing antioxidant and antiviral activity

Stable σ-adducts of azolo[5,1-c]triazines and azolo[1,5-a]pyrimidines with different polyphenols were synthesized and their antioxidant and antiviral activity were investigated. Their affinity to viral hemagglutinin was assessed using molecular modelling. The phloroglucinol-modified azolo-azines possessed the highest virus-inhibiting activity. According to the results of the study of antioxidant properties of compounds, the most promising ones exhibiting highest antioxidant capacity were adducts containing in their structure pyrogallol and catechol residues and 6-nitro-triazolotriazin-7-ol scaffold. No correlation between antioxidant and virus-inhibiting activity of compounds studied was detected. The most active compounds demonstrated the ability to prevent binding of viral hemagglutinin with cellular receptor as shown in hemagglutination inhibition assay. Our results demonstrate that polyphenol-modified azolo-azines are prospective for further optimization as potential antivirals and that their action is directed against viral hemagglutinin.     

Design,RNA cleavage and antiviral activity of new artificial ribonucleases derived from mono-, di- and tripeptides connected by linkers of different hydrophobicity

A novel series of metal-free artificial ribonucleases (aRNases) was designed, synthesized and assessed in terms of ribonuclease activity and ability to inactivate influenza virus WSN/A33/H1N1 in vitro. The compounds were built of two short peptide fragments, which include Lys, Ser, Arg, Glu and imidazole residues in various combinations, connected by linkers of different hydrophobicity (1,12-diaminododecane or 4,9-dioxa-1,12-diaminododecane). These compounds efficiently cleaved different RNA substrates under physiological conditions at rates three to five times higher than that of artificial ribonucleases described earlier and displayed RNase A-like cleavage specificity. aRNases with the hydrophobic 1,12-diaminododecane linker displayed ribonuclease activity 3–40 times higher than aRNases with the 4,9-dioxa-1,12-diaminododecane linker. The assumed mechanism of RNA cleavage was typical for natural ribonucleases, that is, general acid-base catalysis via the formation of acid/base pairs by functional groups of amino acids present in the aRNases; the pH profile of cleavage confirmed this mechanism. The most active aRNases under study exhibited high antiviral activity and entirely inactivated influenza virus A/WSN/33/(H1N1) after a short incubation period of viral suspension under physiological conditions.     

Detecting early-warning signals for influenza A pandemic based on protein dynamical network biomarkers

The outbreak of influenza A comes from a relatively stable state is a critical phenomenon on epidemic. In this paper, influenza A varying from different states is studied in the method of dynamical network biomarkers (DNB). Through studying DNB of influenza A virus protein, we can detect the warning signals of outbreak for influenza A and obtain a composite index. The composite index varies along with the state of pandemic influenza, which gives a clue showing the turn point of outbreak. The low value (<1) steady state of the composite index means influenza A is normally in the relatively steady stage. Meanwhile, if the composite index of a certain year increases by more than 0.8 relative to the previous year and it is less than 1 and it increases sharply and reaches a peak being larger than 1 in next year, it means the year is normal in the critical state before outbreak and the next year is normally in the outbreak state. Therefore, we can predict the outbreak of influenza A and identify the critical state before influenza A outbreak or outbreak state by observing the variation of index value.     

Protective efficacy of mucosal and subcutaneous immunization with DnaJ-ΔA146Ply against influenza and Streptococcus pneumoniae co-infection in mice

Respiratory tract coinfections, specifically involving influenza A virus (IAV) and Streptococcus pneumoniae (S. pneumoniae), remain a major health problem worldwide. Secondary bacterial pneumonia is a common complication and an important cause of mortality related to seasonal and pandemic influenza infections. Vaccination is a basic control strategy against influenza and S. pneumoniae. The fusion protein DnaJ-ΔA146Ply is a vaccine candidate which can induce immune responses against pneumococcal infections via mucosal and subcutaneous immunization in mice. In the present study, we established a co-infection model using mouse-adapted laboratory strains of IAV (PR8) and S. pneumoniae (19F) in mice intranasally and subcutaneously immunized with DnaJ-ΔA146Ply. Our results showed that vaccinated mice suffered decreased weight loss compared with control mice. The survival rates were higher in intranasally and subcutaneously immunized mice than in control mice. In addition, the bacterial loads in nasal washes and lung homogenates were lower in vaccinated mice than in control mice. Furthermore, lung damage was alleviated in vaccinated mice compared with control mice, with less broken alveoli and less proinflammatory cytokine production. Taken together, these results indicate that vaccination with DnaJ-ΔA146Ply shows protective potential against influenza and S. pneumoniae co-infection in mice.     

Effect of adenovirus and influenza virus infection on obesity

The purpose of this review is to provide an overview of the effects of adenovirus and influenza virus infections on obesity in various experimental models. We reviewed studies that were conducted within the past 10 years and were related to virus infection and obesity prevalence. Here, we discuss a different causal relationship between adenovirus and influenza infections with obesity. Adenovirus infection can cause obesity, whereas obesity can be a risk factor for increasing influenza virus infection and increases the risk of morbidity and mortality. The prevalence of obesity due to adenovirus infections may be due to an increase in glucose uptake and reduction in lipolysis caused by an increase in corticosterone secretion. Adenovirus infections may lead to increases in appetite by decreasing norepinephrine and leptin levels and also cause immune dysfunction. The relationship between obesity and influenza virus infection could be summarized by the following features: decreases in memory T-cell functionality and interferon (IFN)-α, IFN-β, and IFN-γ mRNA expression, increases in viral titer and infiltration, and impaired dendritic cell function in obese individuals. Moreover, leptin resistance may play an important role in increasing influenza virus infections in obese individuals. In conclusion, prevention of adenovirus infections could be a good approach for reducing obesity prevalence, and prevention of obesity could reduce influenza virus infections from the point of view of viral infections and obesity.     

Novel derivatives of usnic acid effectively inhibiting reproduction of influenza A virus

Influenza virus is serious human pathogen leading to high morbidity and mortality all over the world. Due to high rate of mutation, it is able to fast development of drug resistance that makes necessary to search novel antivirals with broad range and alternative targets. In the present study we describe synthesis and anti-viral activity of novel derivatives of usnic acid (2,6-diacetyl-7,9-dihydroxy-8,9b-dimethyl-1,3(2H,9bH)-dibenzo-furandione). It is shown that anti-viral activity of usnic acid can be increased by side moieties introduction. The modification with chalcones appeared to be the most effective. Our study revealed that (−)-usnic acid exhibited higher antiviral activity than its (+)-enantiomer, but in the pairs of enantiomer derivatives such as enamines, pyrazoles and chalcones, the (+)-enantiomers were more potent inhibitors of the virus. For other groups of compounds the inhibiting activities of the enantiomers were comparable. Further optimization of the structure could therefore result in development of novel anti-influenza compound with alternative target and mechanism of virus-inhibiting action.     

Influenza entry pathways in polarized MDCK cells

In non-polarized cell culture models, influenza virus has been shown to enter host cells via multiple endocytic pathways, including classical clathrin-mediated endocytic routes (CME), clathrin- and caveolae-independent routes and macropinocytosis. However, little is known about the entry route of influenza virus in differentiated epithelia, in vivo site of infection for influenza virus. Here, we show that in polarized Madin–Darby canine kidney type II (MDCK II) cells, influenza virus has a specific utilization of the clathrin-mediated endocytic pathway and requires Eps15 for host cell entry.     

2018年感染病领域十大进展

2018年已缤纷落幕,2019年带着对未来的期许纷至沓来。回顾过去,展望未来,本文整理了2018年世界乃至中国感染病界的几项重大事件与进展,并进一步梳理了该领域的发展趋势。     

microRNAs与流感病毒感染

MicroRNAs是一类数目庞大,而且可以广泛参与到生命活动各个进程的非编码RNA分子,在病毒感染宿主过程中存在着复杂的microRNAs与病毒的相互作用。流感病毒感染可以引起宿主microRNAs表达谱的明显变化,流感病毒能通过调控某些microRNAs的表达来实现免疫逃逸等增强其感染能力;同时,宿主也可以通过某些microRNAs的变化启动相应的抗流感病毒反应。本文主要针对流感病毒感染过程中宿主-病毒二者在microRNA水平的相互作用进行综述,以期更好的了解流感病毒的致病机制,为抗流感病毒的新药研制提供新的思路。