Michaela Schmidtke

Friedrich Schiller University Jena, Jena, Thuringia, Germany

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Publications (90)279.05 Total impact

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    ABSTRACT: Enteroviruses cause various acute and chronic diseases. The most promising therapeutics for these infections are capsid-binding molecules. These can act against a broad spectrum of enteroviruses, but emerging resistant virus variants threaten their efficacy. All known enterovirus variants with high-level resistance toward capsid-binding molecules have mutations of residues directly involved in the formation of the hydrophobic binding site. This is a first report of substitutions outside the binding pocket causing this type of drug resistance: I1207K and I1207R of the viral capsid protein 1 of coxsackievirus B3. Both substitutions completely abolish the antiviral activity of pleconaril (a capsid-binding molecule) but do not affect viral replication rates in vitro. Molecular dynamics simulations indicate that the resistance mechanism is mediated by a conformational rearrangement of R1095, which is a neighboring residue of 1207 located at the heel of the binding pocket. These insights provide a basis for the design of resistance-breaking inhibitors.
    Antiviral research 09/2015; DOI:10.1016/j.antiviral.2015.09.009 · 3.94 Impact Factor
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    ABSTRACT: There are currently no drugs available for the treatment of enterovirus (EV)-induced acute and chronic diseases such as the common cold, meningitis, encephalitis, pneumonia, and myocarditis with or without consecutive dilated cardiomyopathy. Here, we report the discovery and characterization of pyrazolopyrimidines, a well-tolerated and potent class of novel EV inhibitors. The compounds inhibit the replication of a broad spectrum of EV in vitro with IC50 values between 0.04 and 0.64 μM for viruses resistant to pleconaril, a known capsid-binding inhibitor, without affecting cytochrome P450 enzyme activity. Using virological and genetics methods, the viral capsid was identified as the target of the most promising, orally bioavailable compound 3-(4-trifluoromethylphenyl)amino-6-phenylpyrazolo[3,4-d]pyrimidine-4-amine (OBR-5-340). Its prophylactic as well as therapeutic application was proved for coxsackievirus B3-induced chronic myocarditis in mice. The favorable pharmacokinetic, toxicological, and pharmacodynamics profile in mice renders OBR-5-340 a highly promising drug candidate, and the regulatory nonclinical program is ongoing. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
    ChemMedChem 08/2015; DOI:10.1002/cmdc.201500304 · 2.97 Impact Factor
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    ABSTRACT: The neuraminidase (NA) inhibitor zanamivir (1) is potently active against a broad panel of influenza A and B strains, including mutant viruses, but suffers from pharmacokinetic (PK) shortcomings. Here, distinct prodrug approaches are described that aimed at overcoming zanamivir's lack of oral bioavailability. Lowering the high basicity of the 4-guanidino group in zanamivir and of a bioisosteric 4-acetamidine analog (5) by N-hydroxylation was deemed to be a plausible tactic. The carboxylic acid and glycerol side chain were also masked with different ester groups. The bioisosteric amidine 5 turned out to be potently active against a panel of H1N1 (IC50 = 2-10 nM) and H3N2 (IC50 = 5-10 nM) influenza A viruses (NA inhibition assay). In vitro PK studies showed that all prodrugs were highly soluble, exhibited low protein binding, and were bioactivated by N-reduction to the respective guanidines and amidines. The most promising prodrug candidates, amidoxime ester 7 and N-hydroxyguanidine ester 8, were subjected to in vivo bioavailability studies. Unfortunately, both prodrugs were not orally bioavailable to a convincing degree (F ≤ 3.7%, rats). This finding questions the general feasibility of improving the oral bioavailability of 1 by lipophilicity-increasing prodrug strategies, and suggests that intrinsic structural features represent key hurdles. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.
    Journal of Pharmaceutical Sciences 06/2015; 104(9). DOI:10.1002/jps.24508 · 2.59 Impact Factor
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    ABSTRACT: Aims: In this study, we analyze the challenges involved in detecting novel neuraminidase inhibitors (NAIs) and offer strategies to overcome them with complementary bioassays. Materials & Methods: We investigated the inhibitory activities of NAIs (oseltamivir, zanamivir, DANA, katsumadain A and remazol) as well as non-NAIs (amantadine, nucleozin and rifampicin) on influenzaviral and bacterial (Streptococcus pneumoniae, Clostridium perfringens and Vibrio cholerae) neuraminidases (NAs) with chemiluminescence (CL)- and fluorescence (FL)-based assays. Furthermore, hemagglutination-based NA inhibition assays were established. Results: Our study shows three types of signal interference affecting the readout of biochemical assays: self-FL (katsumadain A and remazol), FL quenching (rifampicin) and CL quenching (rifampicin, remazol, nucleozin and katsumadain A). These challenges were overcome by hemagglutination-based assays. Conclusion: The latter allow a robust performance in discriminating NAIs and non-NAIs.
    Future Virology 02/2015; 10(2):77-88. DOI:10.2217/fvl.14.97 · 1.01 Impact Factor
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    ABSTRACT: Streptococcus (S.) pneumoniae is a major cause of secondary bacterial pneumonia during influenza epidemics. Neuraminidase is a virulence factor of both pneumococci and influenza viruses. Bacterial neuraminidases are structurally related to viral neuraminidases and susceptible to oseltamivir, an inhibitor designed to target viral neuraminidases. This prompted us to evaluate the antipneumococcal potential of two neuraminidase inhibiting natural compounds, the diarylheptanoid katsumadain A and the isoprenylated flavone artocarpin. Chemiluminescence, fluorescence-, and hemagglutination-based enzyme assays were applied to determine the inhibitory efficiency (IC50 value) of the tested compounds towards pneumococcal neuraminidase. The mechanism of inhibition was studied via enzyme kinetics with recombinant NanA neuraminidase. Unlike oseltamivir, which competes with the natural substrate of neuraminidase, artocarpin exhibits a mixed-type inhibition with a Ki value of 9.70 μM. Remarkably, artocarpin was the only neuraminidase inhibitor for which an inhibitory effect in pneumococcal growth (MIC: 0.99–5.75 μM) and biofilm formation (MBIC: 1.15–2.97 μM) was observable. In addition, we discovered that the bactericidal effect of artocarpin can reduce the viability of pneumococci by a factor of >1000, without obvious harm to lung epithelial cells. This renders artocarpin a promising natural product for further investigations.
    International Journal of Medical Microbiology 12/2014; 305(3). DOI:10.1016/j.ijmm.2014.12.004 · 3.61 Impact Factor
  • Oral presentation at the Young Researcher Workshop of the 62nd International Congress and Annual Meeting of the Society for Medicinal Plant and Natural Product Research (GA), Guimarães/PT; 08/2014
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    Nora Seidel · Andreas Sauerbrei · Peter Wutzler · Michaela Schmidtke
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    ABSTRACT: The amino acid substitution of aspartic acid to glycine in hemagglutinin (HA) in position 222 (HA-D222G) as well as HA-222D/G polymorphism of pandemic (H1N1) 2009 influenza viruses (A(H1N1)pdm09) were frequently reported in severe influenza in humans and mice. Their impact on viral pathogenicity and the course of influenza has been discussed controversially and the underlying mechanism remained unclarified. In the present study, BALB/c mice, infected with the once mouse lung- and cell-passaged A(H1N1)pdm09 isolate A/Jena/5258/09 (mpJena/5258), developed severe pneumonia. From day 2 to 3 or 4 post infection (p.i.) symptoms (body weight loss and clinical score) continuously worsened. After a short disease stagnation or even recovery phase in most mice, severity of disease further increased on days 6 and 7 p.i. Thereafter, surviving mice recovered. A 45 times higher virus titer maximum in the lung than in the trachea on day 2 p.i. and significantly higher tracheal virus titers compared to lung on day 6 p.i. indicated changes in the organ tropism during infection. Sequence analysis revealed an HA-222D/G polymorphism. HA-D222 and HA-G222 variants co-circulated in lung and trachea. Whereas, HA-D222 variant predominated in the lung, HA-G222 became the major variant in the trachea after day 4 p.i. This was accompanied by lower neutralizing antibody titers and broader receptor recognition including terminal sialic acid α-2,3-linked galactose, which is abundant on mouse trachea epithelial cells. Plaque-purified HA-G222-mpJena/5258 virus induced severe influenza with maximum symptom on day 6 p.i. These results demonstrated for the first time that HA-222D/G quasispecies of A(H1N1)pdm09 caused severe biphasic influenza because of fast viral intra-host evolution, which enabled partial antibody escape and minor changes in receptor binding.
    PLoS ONE 08/2014; 9(8):e104233. DOI:10.1371/journal.pone.0104233 · 3.23 Impact Factor
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    ABSTRACT: The emergence of new influenza viruses like the pandemic H1N1 influenza A virus in 2009 (A(H1N1)pdm09) with unpredictable difficulties in vaccine coverage and established antiviral treatment protocols emphasizes the need of new murine models to prove the activity of novel antiviral compounds in vivo. The aim of the present study was to develop a small-scale mathematical model based on easily attainable experimental data to explain differences in influenza kinetics induced by different virus strains in mice. To develop a three-dimensional ordinary differential equation model of influenza dynamics, the following variables were included: (i) viral pathogenicity (P), (ii) antiviral immune defense (D), and (iii) inflammation due to pro-inflammatory response (I). Influenza virus-induced symptoms (clinical score S) in mice provided the basis for calculations of P and I. Both, mono- and biphasic course of mild to severe influenza induced by three clinical A(H1N1)pdm09 strains and one European swine H1N2 virus were comparatively and quantitatively studied by fitting the mathematical model to the experimental data. The model hypothesizes reasons for mild and severe influenza with mono- as well as biphasic course of disease. According to modeling results, the second peak of the biphasic course of infection is caused by inflammation. The parameters (i) maximum primary pathogenicity, (ii) viral infection rate, and (iii) rate of activation of the immune system represent most important parameters that quantitatively characterize the different pattern of virus-specific influenza kinetics.
    Bio Systems 04/2014; 118(1). DOI:10.1016/j.biosystems.2014.02.004 · 1.55 Impact Factor
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    Biophysical Journal 01/2014; 106(2):432a-433a. DOI:10.1016/j.bpj.2013.11.2435 · 3.97 Impact Factor
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    ABSTRACT: With the emergence of oseltamivir-resistant influenza viruses and in view of a highly pathogenic flu pandemic, it is important to develop new anti-influenza agents. Here, the development of neuraminidase (NA) inhibitors that were designed to overcome resistance mechanisms along with unfavorable PK properties is described. Several 5-guanidino- and 5-amidino-based oseltamivir derivatives were synthesized and profiled for their anti-influenza activity and in vitro and in vivo PK properties. Amidine 6 and guanidine 7 were comparably effective against a panel of different A/H1N1 and A/H3N2 strains and also inhibited mutant A/H1N1 neuraminidase. Among different prodrug strategies pursued, a simple amidoxime ethyl ester (9) exhibited a superior PK profile with an oral bioavailability of 31% (rats), which is comparable to oseltamivir (36%). Thus, bioisosteric replacement of the 5-guanidine with an acetamidine - in the form of its N-hydroxy prodrug - successfully tackled the two key limitations of currently used NA inhibitors, as exemplified with oseltamivir.
    Journal of Medicinal Chemistry 01/2014; 57(3). DOI:10.1021/jm401492x · 5.45 Impact Factor
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    ABSTRACT: Human cytomegalovirus (HCMV) can cause life-threatening diseases in neonates and immunocompromised patients. Due to multiple problems caused by the current available drugs development of new antiviral compounds is urgently needed. In this study we characterize the anti-HCMV spectrum and mechanism of action of the N-N '-(bis-5 nitropyrimidyl)dispirotripiperazine derivate 27 (DSTP-27).DSTP-27 exhibited strong antiviral activity against two laboratory HCMV strains with different cell tropism as well as a GCV-sensitive and GCV-resistant clinical isolate in plaque reduction assays and viral growth kinetics. Interestingly, neither infectious nor non-infectious viral particles were observed by electron microscopy. Pre-treatment of cell-free virus with DSTP-27 prevented virus infection. The results from time of addition assays where DTSP-27 was added (i) to cells before infection, (ii) during virus adsorption, or (iii) after adsorption demonstrated an inhibitory effect on early steps of the HCMV replication cycle. This observation was confirmed by immunofluorescence as well as Western blot analysis where reduced levels of the immediate early protein IE1, the processivity factor pUL44, and the tegument protein pp28 were detected. Results from attachment and penetration analyses of prechilled human embryonic lung fibroblasts revealed that virus attachment is not blocked. In addition, DSTP-27 inactivated HCMV by stable binding. Taken together, these results demonstrate that DSTP-27 blocks (i)viral penetration by interacting with the host cell and (ii) inactivates HCMV by interacting with the virus.
    Antimicrobial Agents and Chemotherapy 01/2014; 58(4). DOI:10.1128/AAC.01964-13 · 4.48 Impact Factor
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    ABSTRACT: Neuraminidase (NA), a key enzyme in viral replication, is the first-line drug target to combat influenza. On the basis of a shape-focused virtual screening, the roots of Glycyrrhiza glabra (licorice) were identified as plant species with an accumulation of constituents that show 3D similarities to known influenza NA inhibitors (NAIs). Phytochemical investigation revealed 12 constituents identified as (E)-1-[2,4-dihydroxy-3-(3-methyl-2-butenyl)phenyl]-3-(8-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-yl)-2-propen-1-one (1), 3,4-dihydro-8,8-dimethyl-2H,8H-benzo[1,2-b:3,4-b']dipyran-3-ol (2), biochanin B (3), glabrol (4), glabrone (5), hispaglabridin B (6), licoflavone B (7), licorice glycoside B (8), licorice glycoside E (9), liquiritigenin (10), liquiritin (11), and prunin (12). Eleven of these constituents showed significant influenza virus NA inhibition in a chemiluminescence (CL)-based assay. Additional tests, including (i) a cell-based cytopathic effect inhibition assay (general antiviral activity), (ii) the evaluation of cytotoxicity, (iii) the inhibition of the NA of Clostridium perfringens (CL- and fluorescence (FL)-based assay), and (iv) the determination of self-fluorescence and quenching, provided further perspective on their anti-influenza virus potential, revealing possible assay interference problems and false-positive results. Compounds 1, 3, 5, and 6 showed antiviral activity, most likely caused by the inhibition of NA. Of these, compounds 1, 3, and 6 were highly ranked in shape-focused virtual screening.
    Journal of Natural Products 12/2013; 77(3). DOI:10.1021/np400817j · 3.80 Impact Factor
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    ABSTRACT: Influenza virus neuraminidase (iNA) is a homotetrameric surface protein of the influenza virus and an established target for antiviral drugs. In contrast to neuraminidases (NAs) of other biological systems (non-iNAs), enzymatic activity of iNA is only observed in a quaternary assembly and iNA needs the tetramerization to mediate enzymatic activity. Obviously, differences on a molecular level between iNA and non-iNAs are responsible for this intriguing observation. Comparison between protein structures and multiple sequence alignment allow the identification of differences in amino acid composition in crucial regions of the enzyme, such as next to the conserved D151 and the 150-loop. These differences in amino acid sequence and protein tetramerization are likely to alter the dynamics of the system. Therefore, we performed molecular dynamics simulations to investigate differences in the molecular flexibility of monomers, dimers, and tetramers of iNAs of subtype N1 (avian 2004, pandemic 1918 and pandemic 2009 iNA) and as comparison the non-iNA monomer from Clostridium perfringens. We show that conformational transitions of iNA are crucially influenced by its assembly state. The protein-protein interface induces a complex hydrogen-bonding network between the 110-helix and the 150-loop, which consequently stabilizes the structural arrangement of the binding site. Therefore, we claim that these altered dynamics are responsible for the dependence of iNA's catalytic activity on the tetrameric assembly. Only the tetramerization-induced balance between stabilization and altered local flexibility in the binding site provides the appropriate arrangement of key residues for iNA's catalytic activity.
    Journal of biomolecular Structure & Dynamics 11/2013; 33(1). DOI:10.1080/07391102.2013.855142 · 2.92 Impact Factor
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    ABSTRACT: Simvastatin, a cholesterol-lowering drug, is reported to have immunomodulatory properties that attenuated acute lung injury independent of their major lipid lowering effects. Based on these reports, simvastatin is expected to be used for influenza prophylaxis and treatment. The present study evaluated the efficacy of simvastatin against influenza A/PR/8/34 virus infection in a murine model. In a first study, simvastatin was administered orally. To achieve high plasma levels, intraperitoneal application was used in a second study. Survival, body weight loss, viral titers in lung and trachea, and histologic lung injury were measured. Surprisingly, treatment with simvastatin resulted in lower survival rates and in more distinct body mass loss in comparison to virus-infected control mice. Furthermore, the viral load in lungs and tracheas as well as histopathological lesions were not reduced by simvastatin. Overall, these results showed that simvastatin failed to protect mice against influenza virus infection. J. Med. Virol. © 2013 Wiley Periodicals, Inc.
    Journal of Medical Virology 11/2013; 85(11). DOI:10.1002/jmv.23682 · 2.35 Impact Factor
  • Oral presentation at the Joint Symposium "Trends in natural products research" of the Phytochemical Society of Europe (PSE) and the Austrian Pharmaceutical Society (ÖPhG) at the University Centre Obergurgl/Tyrol, Austria, Book of Abstracts. Leicester: Phytochemical Society of Europe, ISBN 978-0-9565472-3-1, p. 38; 07/2013
  • Oral presentation at the Joint Symposium "Trends in natural products research" of the Phytochemical Society of Europe (PSE) and the Austrian Pharmaceutical Society (ÖPhG) at the University Centre Obergurgl/Tyrol, Austria; 07/2013
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    ABSTRACT: Recent epidemiological developments demonstrated that gene segments of swine influenza A viruses can account for antigenic changes as well as reduced drug susceptibility of pandemic influenza A viruses. This raises questions about the efficacy of preventive measures against swine influenza A viruses. Here, the protective effect of vaccination was compared with that of prophylactic Tamiflu® treatment against two Eurasian swine influenza A viruses. 11-week-old pigs were infected by aerosol nebulisation with high doses of influenza virus A/swine/Potsdam/15/1981 (H1N1/1981, heterologous challenge to H1N1 vaccine strain) and A/swine/Bakum/1832/2000 (H1N2/2000, homologous challenge to H1N2 vaccine strain) in two independent trials. In each trial (i) 10 pigs were vaccinated twice with a trivalent vaccine (RESPIPORC® FLU3; 28 and 7 days before infection), (ii) another 10 pigs received 150 mg/day of Tamiflu® for 5 days starting 12 h before infection, and (iii) 12 virus-infected pigs were left unvaccinated and untreated and served as controls. Both viruses replicated efficiently in porcine respiratory organs causing influenza with fever, dyspnoea, and pneumonia. Tamiflu® treatment as well as vaccination prevented clinical signs and significantly reduced virus shedding. Whereas after homologous challenge with H1N2/2000 no infectious virus in lung and hardly any lung inflammation were detected, the virus titre was not and the lung pathology was only partially reduced in H1N1/1981, heterologous challenged pigs. Tamiflu® application did not affect these study parameters. In conclusion, all tested preventive measures provided protection against disease. Vaccination additionally prevented virus replication and histopathological changes in the lung of homologous challenged pigs.
    PLoS ONE 04/2013; 8(4):e61597. DOI:10.1371/journal.pone.0061597 · 3.23 Impact Factor
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    ABSTRACT: Native high molecular weight hyaluronan (HMW-HA, MW=1×10(6)g/mol) and a thermally degraded low molecular weight hyaluronan (LMW-HA, MW=1.3-1.4×10(5)g/mol) were carboxymethylated providing products with degrees of carboxymethylation (DSCM) of up to 0.8. Sulfation of resulting carboxymethyl hyaluronan (CM-HA) and hyaluronan (HA) was performed by different sulfation procedures enabling the control of the degree of sulfation (DSS) in the obtained new carboxymethyl hyaluronan sulfates (CM-HA-S) and hyaluronan sulfates (HA-S), respectively, in a range between 0.9 and 3.3. Both carboxymethylation and sulfation were found to take place preferentially at the primary hydroxyl groups of HA. The antiviral activity of these synthesized HA derivatives was tested against Herpes simplex virus type 1. Both HA-S and CM-HA-S derivatives with high DSS values of about 3.0 exhibit a strong antiherpetic activity. The CM-HA derivatives were found to be not active and an additional effect of introduced carboxymethyl groups on the antiherpetic activity of CM-HA-S derivatives was not observed. In the case of HA-S, the antiviral efficacy can be correlated with the DSS and becomes stronger with increasing DSS values.
    09/2012; 90(1):608-15. DOI:10.1016/j.carbpol.2012.05.085
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    ABSTRACT: Native high molecular weight hyaluronan (HMW-HA, MW = 1×106 g/mol) and a thermally degraded low molecular weight hyaluronan (LMW-HA, MW = 1.3–1.4 ×105 g/mol) were carboxymethylated providing products with degrees of carboxymethylation (DSCM) of up to 0.8. Sulfation of resulting carboxymethyl hyaluronan (CM-HA) and hyaluronan (HA) was performed by different sulfation procedures enabling the control of the degree of sulfation (DSS) in the obtained new carboxymethyl hyaluronan sulfates (CM-HAS) and hyaluronan sulfates (HA-S), respectively, in a range between 0.9 and 3.3. Both carboxymethylation and sulfation were found to take place preferentially at the primary hydroxyl groups of HA. The antiviral activity of these synthesized HA derivatives was tested against Herpes simplex virus type 1. Both HA-S and CM-HA-S derivatives with high DSS values of about 3.0 exhibit a strong antiherpetic activity. The CM-HA derivatives were found to be not active and an additional effect of introduced carboxymethyl groups on the antiherpetic activity of CM-HA-S derivatives was not observed. In the case of HA-S, the antiviral efficacy can be correlated with the DSS and becomes stronger with increasing DSS values.
    Carbohydrate Polymers 01/2012; 90:608-615. · 4.07 Impact Factor
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    ABSTRACT: The imminent threat of influenza pandemics and repeatedly reported emergence of new drug-resistant influenza virus strains demonstrate the urgent need for developing innovative and effective antiviral agents for prevention and treatment. At present, influenza neuraminidase (NA), a key enzyme in viral replication, spread, and pathogenesis, is considered to be one of the most promising targets for combating influenza. Despite the substantial medical potential of NA inhibitors (NAIs), only three of these drugs are currently on the market (zanamivir, oseltamivir, and peramivir). Moreover, sudden changes in NAI susceptibility revealed the urgent need in the discovery/identification of novel inhibitors. Nature offers an abundance of biosynthesized compounds comprising chemical scaffolds of high diversity, which present an infinite pool of chemical entities for target-oriented drug discovery in the battle against this highly contagious pathogen. This review illuminates the increasing research efforts of the past decade (2000-2011), focusing on the structure, function and druggability of influenza NA, as well as its inhibition by natural products. Following a critical discussion of publications describing some 150 secondary plant metabolites tested for their inhibitory potential against influenza NA, the impact of three different strategies to identify and develop novel NAIs is presented: (i) bioactivity screening of herbal extracts, (ii) exploitation of empirical knowledge, and (iii) computational approaches. This work addresses the latest developments in theoretical and experimental research on properties of NA that are and will be driving anti-influenza drug development now and in the near future.
    Natural Product Reports 01/2012; 29(1):11-36. DOI:10.1039/c1np00053e · 10.11 Impact Factor

Publication Stats

1k Citations
279.05 Total Impact Points


  • 1995–2015
    • Friedrich Schiller University Jena
      • • Institute of Virology and Antiviral Therapy
      • • Center of Outpatient Medicine
      • • Institute of Ecology
      Jena, Thuringia, Germany
  • 2011
    • University of Innsbruck
      • Department of Pharmacology
      Innsbruck, Tyrol, Austria
  • 2008–2009
    • Universitätsklinikum Jena
      • Institute of Virology and Antiviral Therapy
      Jena, Thuringia, Germany
  • 2007
    • Fayetteville State University
      Fayetteville, New York, United States