Inhibition of influenza and parainfluenza virus replication in tissue culture by 2-deoxy-2,3-dehydro-N-trifluoroacetylneuraminic acid (FANA)

Palese, Peter; Schulman, Jerome L.; Bodo, G.; Meindl, Peter

doi:10.1016/0042-6822(74)90458-9

Cited by 118 publications

(61 citation statements)

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“…Neuraminidase, a specific glycoprotein on the surface of the influenza virus, is essential for viral replication due to its role in facilitating the release of progeny virions from infected cells. 32) It is a valid drug target for the development of antiinfluenza therapeutics. In our initial neuraminidase inhibition assay, baicalin to some extent inhibited neuraminidase activity (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Inhibitory Effects of Baicalein on the Influenza Virus in Vivo Is Determined by Baicalin in the Serum

Dou

Zhang

et al. 2010

Biological & Pharmaceutical Bulletin

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Baicalein (5,6,7-trihydroxyflavone) is a flavonoid derived from the root of Scutellaria baicalensis, a traditional Chinese medicine used for hundreds of years. This flavonoid demonstrates a variety of biological activities, such as antibacterial, antiinflammatory, antioxidant, antitumor, antiproliferative, anticoagulant, and vascular-protective effects. 1,2) Baicalein is also an inhibitor of reverse transcriptase of the human immunodeficiency virus (HIV), interferes with the RNA replication of HIV, and induces apoptosis in infected cells in vitro.3) Baicalein is the most potent inhibitor of the human cytomegalovirus (HCMV), displaying an IC 50 value of 0.4Ϯ0.04 mM in the colorimetric assay and 1.2Ϯ0.8 mM in the titer reduction assay. It also significantly reduces the levels of early and late proteins of HCMV, as well as viral DNA synthesis. 4)Influenza, one of the major pandemic diseases worldwide, represents a grave threat to human health. At present, only two types of chemical drug are used clinically in the treatment of influenza. One type is the M2 proton channel blockers (amantadine and rimantadine), and the other is neuraminidase inhibitors (zanamivir and oseltamivir). However, resistance to these drugs has been reported. [5][6][7][8] Furthermore, the high price and lack of a sufficient supply prevent oseltamivir (Tamiflu) from being widely used in developing countries. Traditional Chinese medicine, which is widespread in nature with good efficacy, is beginning to play a more important role in this area.It has been reported that baicalein demonstrates inhibitory effects on viruses and that more than 90% of baicalein is rapidly metabolized into baicalin, which is transported to the mesenteric blood when perfused through the rat jejunum. 9,10) However, the mechanism of its antiviral effect is unknown. Here, we report for the first time that baicalein has an inhibitory effect on the influenza virus A/FM1/1/47(H1N1) in vivo and that this effect is mainly due to its metabolite baicalin in serum. MATERIALS AND METHODSReagents Baicalein was a gift from Prof. Qinglong Guo of the Deptartment of Physiology, China Pharmaceutical University. It was dissolved in 0.5% sodium carboxymethyl cellulose (CMC) for in vivo experiments and in dimethyl sulfoxide (DMSO) for in vitro tests. Ribavirin injection was obtained from the China Pharmaceutical University Pharmaceutical Co., Ltd., Nanjing, China. Reference samples of baicalein and baicalin used in HPLC analysis were obtained from the National Institution for the Control of Pharmaceutical and Biological Products, China. Methanol, acetonitrile, and phosphoric acid (HPLC grade) were purchased from Sinopharm Chemical Reagent Co., Ltd., Shanghai, China. Virus and CellsThe influenza A/FM1/1/47(H1N1) virus used in this study was preserved in the Department of Microbiology, School of Life Science and Technology, China Pharmaceutical University. The virus was grown in the allantoic cavity of 10-d-old embryonated hen eggs at 37°C for 2 d.11) The allantoic fluid was harvested and fil...

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Section: Discussionmentioning

confidence: 99%

Inhibitory Effects of Baicalein on the Influenza Virus in Vivo Is Determined by Baicalin in the Serum

Dou

Zhang

et al. 2010

Biological & Pharmaceutical Bulletin

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“…Na corrente sangüínea, os vírus atacam as células 30 (B, Figura 10). Duas principais enzimas virais estão envolvidas no processo de infecção: a hemaglutinina 33,34 e a neuraminidase [35][36][37][38] (Figuras 8 e 10). Ambas as enzimas atuam e reconhecem resíduos de ácidos siálicos presentes nas glicoproteínas das células a serem infectadas e induzem a fusão e incorporação do envelope viral pela célula (C, Figura 10).…”

Section: Compreender Para Combater -O Ciclo De Vida Do Vírus Influenzunclassified

Ácidos siálicos: da compreensão do seu envolvimento em processos biológicos ao desenvolvimento de fármacos contra o agente etiológico da gripe

Fátima¹,

Baptistella²,

Pilli³

et al. 2005

Quím. Nova

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Recebido em 4/2/04; aceito em 13/7/04; publicado na web em 23/11/04 SIALIC ACIDS -FROM THE COMPREHENSION OF THEIR INVOLVEMENT IN BIOLOGICAL PROCESSES TO ANTIINFLUENZA DRUG DESIGN. Sialic acids are nine-carbon carbohydrates that occur widely in nature and occupy the terminal portions of some glycoproteins and glycolipids of cell membranes. These carbohydrates are closely involved in cell-cell interactions and in processes such as microbial infection, inflammation, etc. Studies on the participation of sialic acids in biological processes have provided comprehension about their role in the infection by the influenza virus, the causal agent of flu. In this article, we present an overview of the importance of sialic acids in the influenza virus infection and how the knowledge of their involvement in this process has allowed the development of selective and efficient drugs against the virus.Keywords: sialic acid; flu and antiinfluenza drugs. INTRODUÇÃONão há vida sem célula. E a exemplo da própria vida, que tanta diversidade apresenta, variam as formas e funções das células. As células são as unidades estruturais e funcionais de todos os organismos e é possível reconhecer, em sua hierarquia estrutural, alguns níveis de complexidade, como aqueles presentes, por exemplo, em uma célula vegetal: o nível 3 onde se incluem complexos supramoleculares (cromossomo, membrana plasmática, parede celular, etc); o nível 2 representado por macromoléculas (DNA, proteínas, celulose, etc) e o nível 1 compreendendo as unidades monoméricas, como nucleotídeos, aminoácidos, carboidratos, etc 1-3 (Figura 1).A membrana plasmática, presente em células de todas as espécies, define a periferia da célula, separando o seu conteúdo da circunvizinhança. Ela serve como uma barreira de permeabilidade, que permite à célula manter uma composição citoplasmática e é composta de grande número de moléculas de lipídios e proteínas que se mantêm juntas principalmente por interações hidrofóbicas, formando uma bicamada lipídica fina, resistente e flexível, em volta da célula 1-3 . Algumas proteínas presentes na membrana celular permitem a passagem de certos íons e moléculas (proteínas transportadoras). Outras proteí-nas exercem o papel de receptores, transmitindo o sinal do exterior para o interior da célula. Há ainda proteínas que funcionam como enzimas, participando de reações que ocorrem em membranas.

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“…In structure-activity relationship studies it was found that if the N-acetyl group is replaced with N-fluoro, N-difluoro, Ntrifluoro, or N-chloroacetyl moieties, inhibitory activity is increased (Meindl et al, 1974). DANA and its N-trifluoro derivative, FANA (Figure 16), inhibit the replication of influenza and parainfluenza viruses in tissue culture (Meindl et al, 1971;Palese et al, 1974b;Schulman & Palese, 1975). Interestingly, it was demonstrated that influenza A/NWS, which has an N1 NA, was 50-to 100-fold more susceptible to inhibition by FANA than were influenza viruses containing an N2 NA.…”

Section: Inhibition Of Assembly and Releasementioning

confidence: 99%

“…Importantly, the strain differences were due only to the differences in NA and not in HA. The specificity of FANA was demonstrated by its lack of activity against viruses that do not have NA, including measles virus and vesicular stomatitis virus (Palese et al, 1974b); Kilbourne et al, 1975). Furthermore, electron microscopy of cells infected with influenza and treated with FANA revealed aggregates of virus particles containing envelope-associated neuraminic acid, thus phenotypically resembling temperature-sensitive mutants of influenza that are deficient in NA activity at the non-permissive temperature (Palese & Compans, 1976).…”

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confidence: 99%

Approaches and Strategies for the Treatment of Influenza Virus Infections

Colacino

Staschke

Laver

1999

Antivir Chem Chemother

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Influenza A and B viruses belong to theOrthomyxoviridae family of viruses. These viruses are responsible for severe morbidity and significant excess mortality each year. Infection with influenza viruses usually leads to respiratory involvement and can result in pneumonia and secondary bacterial infections. Vaccine approaches to the prophy-laxis of influenza virus infections have been problematic owing to the ability of these viruses to undergo antigenic shift by exchanging genomic segments or by undergoing antigenic drift, consisting of point mutations in the haemagglutinin (HA) and neuraminidase (NA) genes as a result of an error-prone viral polymerase. Historically, antiviral approaches for the therapy of both influenza A and B viruses have been largely unsuccessful until the elucidation of the X-ray crystallographic structure of the viral NA, which has permitted structure-based drug design of inhibitors of this enzyme. In addition, recent advances in the elucidation of the structure and complex function of influenza HA have resulted in the discovery of a number of diverse compounds that target this viral protein. This review article will focus largely on newer antiviral agents including those that inhibit the influenza virus NA and HA. Other novel approaches that have entered clinical trials or been considered for their clinical utility will be mentioned. Keywords: Influenza virus; haemagglutinin; neuraminidase; amantadine; ribavirin; zanamivir; GS 4104Infection with influenza viruses can result in an infectious disease for which there is no adequate control. Killed influenza vaccines against this virus have been available for nearly 70 years but, on a community-wide basis, the use of these vaccines has not resulted in a significant decrease in the morbidity or mortality of this disease and has not alleviated the severe financial loss which occurs as a result of hospitalizations and lost productivity. Currently, the only compounds approved by the US FDA for the treatment of influenza infections are amantadine and rimantadine, both of which target the M2 ion channel protein of the virus (Pinto et al., 1992). However, these compounds are not effective against influenza B virus, which does not have an M2 ion channel. Also, virus mutants resistant to amantadine or rimantadine can be isolated readily from individuals treated with these drugs Hayden et al., 1989). Recently, it has been suggested that resistance to amantadine can be overcome by mixing amantadine with other amantadine derivatives that interfere with the ion channel function of M2 from amantadine-resistant viruses (Scholtissek et al., 1998). Ribavirin, a broad-spectrum antiviral agent Witkowski et al., 1972;Huffman et al., 1973;Oxford, 1975) has been considered for use against influenza A and B viruses, but the clinical trials of this compound have not been encouraging (Cohen et al., 1976;Togo & McCracken, 1976;Magnussen et al., 1977;Smith et al., 1980;Stein et al., 1987) and it has not been approved for the treatment of influenza virus infection.Hist...

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Inhibition of influenza and parainfluenza virus replication in tissue culture by 2-deoxy-2,3-dehydro-N-trifluoroacetylneuraminic acid (FANA)

Cited by 118 publications

References 14 publications

Inhibitory Effects of Baicalein on the Influenza Virus in Vivo Is Determined by Baicalin in the Serum

Inhibitory Effects of Baicalein on the Influenza Virus in Vivo Is Determined by Baicalin in the Serum

Ácidos siálicos: da compreensão do seu envolvimento em processos biológicos ao desenvolvimento de fármacos contra o agente etiológico da gripe

Approaches and Strategies for the Treatment of Influenza Virus Infections

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