多糖抗病毒作用研究进展Ⅱ.硫酸多糖抗病毒作用

硫酸多糖的抗病毒活性,包括抗艾滋病毒HIV1活性,在近年得以阐明。本文综述了硫酸多糖的抗病毒作用、抗病毒机理及其构效关系。硫酸多糖具有广阔的临床应用前景,其抗病毒作用值得深入研究。     

Antiviral Potential of Lactic Acid Bacteria and Their Bacteriocins

Emerging resistance to antiviral agents is a growing public health concern worldwide as it was reported for respiratory, sexually transmitted and enteric viruses. Therefore, there is a growing demand for new, unconventional antiviral agents which may serve as an alternative to the currently used drugs. Meanwhile, published literature continues shedding the light on the potency of lactic acid bacteria (LAB) and their bacteriocins as antiviral agents. Health-promoting LAB probiotics may exert their antiviral activity by (1) direct probiotic–virus interaction; (2) production of antiviral inhibitory metabolites; and/or (3) via stimulation of the immune system. The aim of this review was to highlight the antiviral activity of LAB and substances they produce with antiviral activity.     

猪γ干扰素的表达及其抗病毒活性的安全检测

为了提高干扰素抗病毒活性测定的生物安全性,本研究使用含有GFP的复制缺陷型水疱性口炎病毒(VSV△G*G)为指示病毒,分别对经原核表达系统和杆状病毒表达系统表达的重组猪γ干扰素(PoIFN-γ)在MDBK细胞上进行抗病毒活性测定。结果显示:由杆状病毒表达的重组PoIFN-γ具有高度抗病毒活性,其抗病毒活性为105IU/mL,原核表达的重组PoIFN-γ纯化后经缓慢复性也会产生一定的抗病毒活性,其抗病毒活性为32IU/mL。该方法与利用表达GFP的重组水疱性口炎病毒(VSV*GFP)所检测的干扰素抗病毒活性结果完全一致,表明复制缺陷型病毒VSV△G*G可作为复制型重组病毒的替代品,使得干扰素抗病毒活性检测更加安全、准确。     

Analysis and Prediction of Highly Effective Antiviral Peptides Based on Random Forests

The goal of this study was to examine and predict antiviral peptides. Although antiviral peptides hold great potential in antiviral drug discovery, little is done in antiviral peptide prediction. In this study, we demonstrate that a physicochemical model using random forests outperform in distinguishing antiviral peptides. On the experimental benchmark, our physicochemical model aided with aggregation and secondary structural features reaches 90% accuracy and 0.79 Matthew''s correlation coefficient, which exceeds the previous models. The results suggest that aggregation could be an important feature for identifying antiviral peptides. In addition, our analysis reveals the characteristics of the antiviral peptides such as the importance of lysine and the abundance of α-helical secondary structures.     

The role of interferon-beta 1 and the 26-kDa protein (interferon-beta 2) as mediators of the antiviral effect of interleukin 1 and tumor necrosis factor

This study confirms our earlier finding that human interleukin (IL)-1 beta exerts an antiviral effect on diploid fibroblasts and on MG-63 osteosarcoma cells. It also extends the observation in that a similar effect was noted on aged but not freshly trypsinized HEp-2 cells, and that not only IL-1 beta but also IL-1 alpha and tumor necrosis factor (TNF)-alpha exerted similar antiviral effects on cells. The antiviral effects of these cytokines were neutralized by addition to the assay system of an antibody that was specific for interferon (IFN)-beta 1, indicating that IFN-beta 1 or a structurally or functionally related substance is involved in the antiviral activity observed. Both IL-1 and TNF were able to induce production of the 26-kDa protein, also known as IFN-beta 2, hybridoma/plasmacytoma growth factor (HPGF) or B-cell stimulatory factor-2 (BSF-2) and previously proposed as an alternative to IFN-beta 1 for mediating the antiviral effect of TNF. However, no good correlation was found between the antiviral effects of TNF and its potential to induce production of the 26-kDa protein. Furthermore, the anti-IFN-beta 1 serum which neutralized the antiviral activity of IL-1 and TNF did not cross-react with the 26-kDa protein. Conversely, the antiviral effect of IL-1 and TNF was only weakly neutralized by an antibody that did react with the 26-kDa protein and showed low cross-reactivity with IFN-beta 1. These observations, together with the low specific activity of the 26-kDa protein as an antiviral agent (less than 10(5) U/mg protein) provide strong arguments against this protein and in favor of IFN-beta 1 (or still another IFN-beta 1-related molecule) as the ultimate mediator of the antiviral effect of IL-1 and TNF.     

Mammalian antiviral systems directed by small RNA

There are strong incentives for human populations to develop antiviral systems. Similarly, genomes that encode antiviral systems have had strong selective advantages. Protein-guided immune systems, which have been well studied in mammals, are necessary for survival in our virus-laden environments. Small RNA–directed antiviral immune systems suppress invasion of cells by non-self genetic material via complementary base pairing with target sequences. These RNA silencing-dependent systems operate in diverse organisms. In mammals, there is strong evidence that microRNAs (miRNAs) regulate endogenous genes important for antiviral immunity, and emerging evidence that virus-derived nucleic acids can be directly targeted by small interfering RNAs (siRNAs), PIWI-interacting RNAs (piRNAs), and transfer RNAs (tRNAs) for protection in some contexts. In this review, we summarize current knowledge of the antiviral functions of each of these small RNA types and consider their conceptual and mechanistic overlap with innate and adaptive protein-guided immunity, including mammalian antiviral cytokines, as well as the prokaryotic RNA-guided immune system, CRISPR. In light of recent successes in delivery of RNA for antiviral purposes, most notably for vaccination, we discuss the potential for development of small noncoding RNA–directed antiviral therapeutics and prophylactics.     

Early Viral Entry Assays for the Identification and Evaluation of Antiviral Compounds

Cell-based systems are useful for discovering antiviral agents. Dissecting the viral life cycle, particularly the early entry stages, allows a mechanistic approach to identify and evaluate antiviral agents that target specific steps of the viral entry. In this report, the methods of examining viral inactivation, viral attachment, and viral entry/fusion as antiviral assays for such purposes are described, using hepatitis C virus as a model. These assays should be useful for discovering novel antagonists/inhibitors to early viral entry and help expand the scope of candidate antiviral agents for further drug development.     

Characterization of translational inhibitors from Phytolacca americana. Amino-terminal sequence determination and antibody-inhibitor conjugates

Two translational inhibitors (pokeweed antiviral protein and pokeweed antiviral protein II) isolated from the leaves of the pokeweed plant, Phytolacca americana, were characterized as to their behavior during reverse-phase HPLC and their amino-terminal sequences. Alignment of the sequences demonstrated that a substantial degree of homology was present (10 of 29 identical residues). Pokeweed antiviral protein was shown by reverse-phase chromatography to be composed of at least two components, pokeweed antiviral proteina and pokeweed antiviral proteinb, which comigrated on sodium dodecyl sulfate polyacrylamide gel electrophoresis, shared identical N-terminal amino-acid sequences through residue 31, and had similar specific activities in a cell-free translation inhibition assay. Pokeweed antiviral protein II was covalently coupled to a monoclonal antibody that recognizes the transferrin receptor (anti-transferrin receptor). The disulfide-linked conjugate inhibited protein synthesis in the human breast tumor cell line MCF-7, whereas anti-transferrin receptor, pokeweed antiviral protein II, or an immunotoxin composed of an irrelevant antiserum and pokeweed antiviral protein II, were nontoxic. The inhibitory dose 50% of anti-transferrin receptor-pokeweed antiviral protein II for MCF-7 cells was 0.7 nM, whereas the corresponding ricin A chain conjugate (anti-transferrin receptor-ricin A chain) was more potent with a inhibitory dose 50% of 0.1 nM. Pokeweed antiviral protein II can be added to the growing list of translation inhibitors that are effective as components of immunotoxins in vitro. Additional studies will be needed to determine whether pokeweed antiviral protein II immunotoxins provide advantageous properties for in vivo applications.     

Antiviral Therapy

The current status of antiviral therapy is reviewed, including discussion of older approaches together with more recently developed chemotherapy. Following the introduction dealing with pathophysiological aspects of virus disease, the different approaches to antiviral therapy are presented. The reasons for the slow progress in antiviral therapy are discussed. These include: 1. the necessity of intracellular penetration of drugs acting on viral replication; 2. the severe toxicity of most antiviral drugs; 3. the narrow antiviral spectrum of most of these agents; 4. the difficulty of making a rapid etiological diagnosis in view of the necessity of starting (specific?) treatment early in the course of the disease; 5. the difficult evaluation of beneficial as compared with deleterious effects of antiviral therapy. After a detailed review of clinically tested substances, including immunoglobulins, synthetic antiviral drugs (amantadine, nucleoside analogs, thiosemicarbazones and photodynamic dyes) and interferon, a guide concerning indications and application of specific antiviral therapy is presented. Although at present there are few indications, clinicians should be aware of the (present and future) possibilities of antiviral therapy.     

Structural Requirements for the Antiviral Activity of the Human MxA Protein against Thogoto and Influenza A Virus

The interferon-induced dynamin-like MxA protein has broad antiviral activity against many viruses, including orthomyxoviruses such as influenza A and Thogoto virus and bunyaviruses such as La Crosse virus. MxA consists of an N-terminal globular GTPase domain, a connecting bundle signaling element, and the C-terminal stalk that mediates oligomerization and antiviral specificity. We previously reported that the disordered loop L4 that protrudes from the compact stalk is a key determinant of antiviral specificity against influenza A and Thogoto virus. However, the role of individual amino acids for viral target recognition remained largely undefined. By mutational analyses, we identified two regions in the C-terminal part of L4 that contribute to an antiviral interface. Mutations in the proximal motif, at positions 561 and 562, abolished antiviral activity against orthomyxoviruses but not bunyaviruses. In contrast, mutations in the distal motif, around position 577, abolished antiviral activity against both viruses. These results indicate that at least two structural elements in L4 are responsible for antiviral activity and that the proximal motif determines specificity for orthomyxoviruses, whereas the distal sequence serves a conserved structural function.     

Self-Interest versus Group-Interest in Antiviral Control

Antiviral agents have been hailed to hold considerable promise for the treatment and prevention of emerging viral diseases like H5N1 avian influenza and SARS. However, antiviral drugs are not completely harmless, and the conditions under which individuals are willing to participate in a large-scale antiviral drug treatment program are as yet unknown. We provide population dynamical and game theoretical analyses of large-scale prophylactic antiviral treatment programs. Throughout we compare the antiviral control strategy that is optimal from the public health perspective with the control strategy that would evolve if individuals make their own, rational decisions. To this end we investigate the conditions under which a large-scale antiviral control program can prevent an epidemic, and we analyze at what point in an unfolding epidemic the risk of infection starts to outweigh the cost of antiviral treatment. This enables investigation of how the optimal control strategy is moulded by the efficacy of antiviral drugs, the risk of mortality by antiviral prophylaxis, and the transmissibility of the pathogen. Our analyses show that there can be a strong incentive for an individual to take less antiviral drugs than is optimal from the public health perspective. In particular, when public health asks for early and aggressive control to prevent or curb an emerging pathogen, for the individual antiviral drug treatment is attractive only when the risk of infection has become non-negligible. It is even possible that from a public health perspective a situation in which everybody takes antiviral drugs is optimal, while the process of individual choice leads to a situation where nobody is willing to take antiviral drugs.     

Long noncoding RNA AANCR modulates innate antiviral responses by blocking miR-210-dependent MITA downregulation in teleost fish,Miichthys miiuy

Viral infection induces the initiation of antiviral effectors and cytokines which are critical mediators of innate antiviral responses.The critical molecular determinants are responsible for triggering an appropriate immune response. Long noncoding RNAs(lncRNAs) have emerged as new gene modulators involved in various biological processes, while how lncRNAs operate in lower vertebrates are still unknown. Here, we discover a long noncoding RNA, termed antiviral-associated long noncoding RNA(AANCR), as a novel regulator for innate antiviral responses in teleost fish. The results indicate that fish MITA plays an essential role in host antiviral responses and inhibition of Siniperca chuatsi rhabdovirus(SCRV) production. miR-210 reduces MITA expression and suppress MITA-mediated antiviral responses, which may help viruses evade host antiviral responses. Further,AANCR functions as a competing endogenous RNA(ceRNA) for miR-210 to control protein abundance of MITA, thereby inhibiting SCRV replication and promoting antiviral responses. Our data not only shed new light on understanding the function role of lncRNA in biological processes in teleost fish, but confirmed the hypothesis that ceRNA networks exist widely in vertebrates.     

Mitochondria and antiviral innate immunity

Mitochondria, dynamic organelles that undergo continuous cycles of fusion and fission, are the powerhouses of eukaryotic cells. Recent research indicates that mitochondria also act as platforms for antiviral immunity in vertebrates. Mitochondrial-mediated antiviral immunity depends on activation of the retinoic acid-inducible gene I (RIG-I)-like receptors signal transduction pathway and the participation of the mitochondrial outer membrane adaptor protein “mitochondrial antiviral signaling (MAVS)”. Here we discuss recent findings that suggest how mitochondria contribute to antiviral innate immunity.     

Approaches to antiviral drug development

At present, only a few drugs have been approved by the FDA for therapy of viral infections in humans. There is a great need for antiviral drugs with increased potency and decreased toxicity, as well as drugs to treat viral diseases for which no drug or vaccine is currently available. Two approaches for development of antiviral drugs are described--an empirical strategy and a rational strategy--with several examples of each. Although many compounds have potent antiviral activity in cell culture, only a small fraction of these will go on to become antiviral drugs for use in humans. At this time, only seven synthetic compounds and alpha interferon have been approved by the FDA for therapy of viral infections in humans. None of these approved drugs are without toxicities, however, and hence there is a great need for antiviral drugs with increased potency and decreased toxicity, as well as for drugs to treat viral diseases for which no drug or vaccine is currently available. Two approaches for the development of antiviral drugs--the empirical and the rational strategies--and their applications and future directions are discussed.     

Virus perception at the cell surface: revisiting the roles of receptor-like kinases as viral pattern recognition receptors

Activation of antiviral innate immune responses depends on the recognition of viral components or viral effectors by host receptors. This virus recognition system can activate two layers of host defence, pathogen-associated molecular pattern (PAMP)-triggered immunity (PTI) and effector-triggered immunity (ETI). While ETI has long been recognized as an efficient plant defence against viruses, the concept of antiviral PTI has only recently been integrated into virus–host interaction models, such as the RNA silencing-based defences that are triggered by viral dsRNA PAMPs produced during infection. Emerging evidence in the literature has included the classical PTI in the antiviral innate immune arsenal of plant cells. Therefore, our understanding of PAMPs has expanded to include not only classical PAMPS, such as bacterial flagellin or fungal chitin, but also virus-derived nucleic acids that may also activate PAMP recognition receptors like the well-documented phenomenon observed for mammalian viruses. In this review, we discuss the notion that plant viruses can activate classical PTI, leading to both unique antiviral responses and conserved antipathogen responses. We also present evidence that virus-derived nucleic acid PAMPs may elicit the NUCLEAR SHUTTLE PROTEIN-INTERACTING KINASE 1 (NIK1)-mediated antiviral signalling pathway that transduces an antiviral signal to suppress global host translation.     

Rapid synthesis of 2′,3′-dideoxy-3′β-fluoro-pyrimidine nucleosides from 2′-deoxypyrimidine nucleosides

A rapid synthesis of 2′,3′-dideoxy-3′-fluoro-β-d-threo-nucleosides bearing the pyrimidine canonical bases of nucleic acids has been developed in order to discover new nucleoside derivatives as potential antiviral drugs. However, when evaluated for their antiviral activity in cell culture experiments, none of these compounds showed any significant antiviral activity.     

Two groups of rhinoviruses revealed by a panel of antiviral compounds present sequence divergence and differential pathogenicity.

A variety of chemically different compounds inhibit the replication of several serotypes of rhinoviruses (common-cold viruses). We noticed that one of these antiviral compounds, WIN 51711, had an antiviral spectrum clearly distinctive from a consensus spectrum or other capsid-binding compounds, although all of them were shown to share the same binding site. A systematic evaluation of all known rhinovirus capsid-binding compounds against all serotyped rhinoviruses was therefore initiated. Multivariate analysis of the results revealed the existence of two groups of rhinoviruses, which we will call antiviral groups A and B. The differential sensitivity of members of these groups to antiviral compounds suggests the existence of a dimorphic binding site. The antiviral groups turned out to be a reflection of a divergence of rhinovirus serotypes on a much broader level. Similarities in antiviral spectra were highly correlated with sequence similarities, not only of amino acids lining the antiviral compound-binding-site, but also of amino acids of the whole VP1 protein. Furthermore, analysis of epidemiological data indicated that group B rhinoviruses produced more than twice as many clinical infections per serotype than group A rhinoviruses did. Rhinoviruses belonging to the minor receptor group were without exception all computed to lie in the same region of antiviral group B.     

Molnupiravir,favipiravir and other antiviral drugs with proposed potentials for management of COVID-19: a concern on antioxidant aspect

COVID-19 is an important global public health problem that causes millions of infections worldwide. The specific antiviral drug for this new infection is still under research. Some new antiviral drugs, including molnupiravir and favipiravir, are proposed for usefulness in management of COVID-19. Additionally, some classic antiviral drugs used for other viral infections are also reproposed for the potentials for management of COVID-19. In the management of COVID-19, there are several pharmacological actions. An important consideration in antiviral therapy is the management of oxidative stress, which plays important roles in viral infections including to COVID-19. The analysis of antioxidative properties of alternative drugs for management of COVID-19 is interesting and can give basic data for further new antiviral drug researching. Here, the authors perform a molecular analysis on molnupiravir, favipiravir and other antiviral drugs with proposed potentials for management of COVID-19 to determine their antioxidative properties. Data from electron acceptor and donor calculation for each drug is used for further estimating overall antioxidative characteristic. Based on the present study, all studied drugs have overall antioxidative properties. Hence, the advantage of molnupiravir, favipiravir and other antiviral drugs with proposed potentials for the management of COVID-19 is their direct action on viral molecule via binding-blocking process as well as antixodiative process. For management of COVID-19 antioxidative stress, other non-antiviral drugs that are proposed for clinical advantage might also be useful.