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FWF-Project P24587

Project period: 2012 - 2015

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Project Leader:

A. Univ.-Prof. Dr. Judith M. Rollinger

Institute of Pharmacy/Pharmacognosy
University of Innsbruck

Center for Chemistry and Biomedicine
Innrain 80-82, R. No L.04.032
A-6020 Innsbruck, Austria

Tel: +43 512 507 58407 / 58499 (fax)
Email: Judith.Rollinger@uibk.ac.at


Project


Team
/Collaborations


News / Publications

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The Project

The respiratory influenza viruses A and B remain a significant global health challenge by causing annual seasonal flu, occasional epidemics and pandemics. These threats in combination with the propensity of influenza viruses to develop resistance to commonly used drugs require the continued development of new antiviral agents. This project aims at the identification of novel anti-influenza agents from natural sources targeting two influenza virus proteins, namely the neuraminidase (NA) and the nucleoprotein (NP). These two targets are highly conserved and cover various stages of viral life cycle. Novel agents against NA and NP shall help to overcome resistance and to develop multidrug strategies.

Inhibition of the influenza virus NA impedes the release of newly formed virions from infected cells and causes viral aggregation, thus halting the spread of infection. The high amount of data and information of this established drug target and its ligands will be used as starting point to apply structure-based· computational methods to cope with the flexibility of the NA binding site·(Grienke·et·al. 2010,·doi 10.1021/jm901440f), and to scrutinize its ligand-target interactions for the discovery of ligands that overcome the influence of mutational changes conferring drug resistance.

workflow1

In contrast to NA, the influenza nucleoprotein (NP) only recently emerged as druggable target for potential small molecule therapies. Ligands of this abundantly expressed protein are found to impede influenza A virus replication by triggering the aggregation of NP and inhibition of its nuclear accumulation. Based on previously published compounds interacting on the NP, a ligand-based approach will be the rationale for the target-oriented identification of putative NP-ligands from the rich pool of secondary metabolites.

The selection of natural starting materials for phytochemical investigations will depend on

(i) virtually predicted hits form ligand- and structure-based approaches

(ii) previously determined anti-influenza or anti-viral activities of herbal remedies or constituents thereof (with unknown mechanism of action) and

(iii) empirical knowledge of antiviral herbal remedies form traditional medicine.

Based on these selection criteria, in depth analytical and phytochemical studies will be performed with most promising natural starting materials for each target, primarily from plant origin. Fractions enriched with virtually predicted hits and finally isolated and identified compounds will be provided for assaying on the respective anti-influenza targets and determination of their antiviral efficacy.

workflow2

We aim to

(i) explain the anti-influenza molecular mechanism of traditionally approved herbal remedies,

(ii) identify naturally derived drug leads for novel NA-inhibitors with lower risk to develop drug resistance, and

(iii) enrich the pool of small molecule ligands for the innovative anti-influenza target NP in an effort to discover agents for a rapidly evolving pathogen.


The Team

Pharmacognosy Innsbruck:

A. Univ-Prof. Dr. Judith M. Rollinger (PI)

Mag. pharm. Dr. Ulrike Grienke (now back from her PostDoc year in Galway, Ireland)

Mag. pharm. Christina E. Mair (PhD student)

Mag. pharm. Sarah Öttl (PhD student)

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The Collaborators

Virology Group in Jena:

PD Dr. Michaela Schmidtke

Zhongli Xu (PostDoc)

Martina Richter (PhDstudent)

Elisabeth Walther (PhDstudent)

Nora Seidel (PhDstudent)

Anja Hoffmann (PhDstudent)

Kathrin Bohn (PhDstudent)

Birgit Jahn (MTA)


Theoretical Chemistry Group in Innsbruck:

Univ. Prof. Dr. Dr. Klaus Liedl

Christian Kramer (PostDoc)

Susanne von Grafenstein (PhDstudent)

Mag. pharm. Dr. Johannes Kirchmair (PostDoc at ETH Zurich, CH, Computer-Assisted Drug Design Group - Prof. Dr. Gisbert Schneider)

Medicinal Chemistry Group in Moskow:

Dr. Vadim Makarov

News

Kick-off Meeting: 'Neuraminidases for Influenza Therapy' and Workshop

in Jena, Germany, on 18./19.07.2012 : Program

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'Flu Workshop' and Annual Meeting

in Innsbruck, Austria, on 25./26.02.2013: Program

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Flu Workshop' and Annual Meeting

in Innsbruck, Austria, on 30./31.03.2014: Program

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Publications

Papers

Grienke, U.; Braun, H.; Seidel, N.; Kirchmair, J.; Richter, M.; Krumbholz, A.; von Grafenstein, S.; Liedl, K.R.; Schmidtke, M.; Rollinger, J.M. (2014): Computer-guided approach to access the anti-influenza activity of licorice constituents. J. Nat. Prod. (special issue dedicated to Prof. Dr. O. Sticher) 77, 563–570. doi: 10.1021/np400817j.

von Grafenstein, S.; Wallnoefer, H.G.; Kirchmair, J.; Fuchs, J.E.; Huber, R.G.; Schmidtke, M.; Sauerbrei, A.; Rollinger, J.M.; Liedl, K.R. (2013): Interface dynamics explain assembly dependency of influenza neuraminidase catalytic activity. J. Biomol. Struct. Dyn. doi: 10.1080/07391102.2013.855142 (Article in press).

Grienke, U.; Schmidtke, M.; von Grafenstein, S.; Kirchmair, J.; Liedl, K.R.; Rollinger, J.M. (2012): Influenza neuraminidase: A druggable target for natural compounds. Nat. Prod. Rep. 29, 11-36. doi: 10.1039/C1NP00053E (amongst top ten most accessed articles from the online version of Nat. Prod. Rep. in 2012).

Kirchmair, J.; Rollinger, J. M.; Liedl, K. R.; Seidel, N.; Krumbholz, A.; Schmidtke, M. (2011) Identification, biological evaluation and investigations of the binding mode of resistance-braking inhibitors of influenza neuraminidase. Future Med. Chem. 3, 437-450. doi: 10.4155/fmc.10.292

Kirchmair, J.; Distinto, S.; Liedl, K.R.; Markt. P.; Rollinger, J.M., Schuster, D.; Spitzer, G.M.; Wolber, G. (2011) Development of anti-viral agents using molecular modeling and virtual screening techniques. Infect. Disorders-Drug Targets 11, 64-93. doi: 10.2174/187152611794407782

Rollinger, J.M. and Schmidtke, M. (2011) The human rhinovirus - human pathological impact, mechanisms of antirhinoviral agents and strategies for their discovery. Med. Res. Rev. Jan, 31, 42-92. doi: 10.1002/med.20176

Grienke, U.; Schmidtke, M.; Kirchmair, J.; Pfarr, K.; Wutzler, P.; Dürrwald, R.; Wolber, G.; Liedl, K.R.;Stuppner, H.; Rollinger, J.M. (2010): Antiviral potential and molecular insight into neuraminidase inhibiting diarylheptanoids from Alpinia katsumadai. J. Med. Chem. 53, 778-786. doi: 10.1021/jm901440f

Patent

Kirchmair, J.; Schmidtke, M.; Liedl, K.; Rollinger, J.M. (2013): Compounds for the treatment of influenza. Eur. Pat. Appl. EP 2599480 A1 20130605

Talks

Rollinger, J.M. (2014): Das Potential von Naturstoffen auf der Suche nach antiviralen Leitstrukturen, invited lecture at the Forum Virologicum, Friedrich Schiller University of Jena/Germany, April 23, 2014.

Grienke, U.(2014): Alternative strategies to access anti-influenza agents from multi-component natural mixtures. Oral presentation at the 'Flu Workshop' in Innsbruck, Austria.March31, 2014.

Mair, C.E. (2014): Is there a benefit from traditional medicine in a phenotypic antiviral screening? Oral presentation at the 'Flu Workshop' in Innsbruck, Austria. March 31, 2014.

Grienke, U.; Braun, H.; Seidel, N.; Kirchmair, J.; Richter, M.; Krumbholz, A.; von Grafenstein, S.; Liedl, K.R.; Schmidtke, M.; Rollinger, J.M. (2014): Shedding light on the anti-influenza effect of Glycyrrhiza glabra roots: Complex multi-component mixtures versus pure constituents. Oral presentation at the 24th Annual Meeting of the Society for Virology in Alpbach/Tyrol, Austria. March 27, 2014.

Walther, E.; Xu, Z.; Grienke, U.; Kirchmair, J.; Rollinger, J.M.; Sauerbrei, A.; Pfister, W.; Schmidtke, M. (2014):Blocking pneumococcus-enhanced influenza virus spread by dual-targeting neuraminidase inhibitors. Oral presentation at the 24th Annual Meeting of the Society for Virology in Alpbach/Tyrol, Austria. March 26, 2014.

Mair, C.E. (2014): Metabolite profiling and anti-influenza screening of micro-fractions from Capsella bursa-pastoris. Oral presentation at the Jena University Hospital Jena/G, Institute for Virology and Antiviral Therapy, Feb. 10, 2014.

Grienke, U.; Richter, M.; Braun, H.; Kirchmair, J.; von Grafenstein, S.; Liedl, K.R.; Schmidtke, M.; Rollinger, J.M. (2013): New insights into the anti-influenza activity of licorice constituents. 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. July 24, 2013.

Mair, C.E.; Grienke, U.; von Grafenstein, S.; Kirchmair, J.; Liedl, K.R.; Schmidtke, M.; Rollinger, J.M. (2013): Bioprospecting diverse plant species for antiviral agents against upper respiratory tract infections. 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. July 24, 2013.

Rollinger, J.M. (2013) Implementation of traditional medicine into structure based approaches for antiviral lead discovery. Invited key lecture at the annual Meeting of the American Society of Pharmacognosy (ASP) in St. Louis, Missouri, July 16, 2013

Grienke, U. (2013) Comparative studies and challenges faced by different flavonoid scaffolds in anti-viral assays. Oral presentation at the 'Flu Workshop' in Innsbruck, Austria. February 26, 2013. 

Grienke, U. (2012) Targeting Inflammation and Influenza: Integration of Computational Methods into Lead Finding From Natural Sources. Award Lecture on the occasion of the Egon Stahl Award in Bronze at the International Congress on Natural Products Research, New York City, July 30, 2012.

Rollinger, J.M. (2012) Integrated data-mining tools for the identification of natural drug leads. Invited guest lecture at the Department of Chemical Engineering of Aristotle University of Thessaloniki, Greece. Thessaloniki, 5th June 2012

von Grafenstein, S.; Wallnoefer, H.G.; Fuchs, J.E.; Huber, R.G.; Rollinger, J.M.; Kirchmair, J.; Liedl, K.R. (2011) Impact of tetramerization on neuraminidase dynamics and binding site conformations. Oral presentation at the 3rd Life Science Meeting of Innsbruck Universities, Igls, Austria, 23.-24.09.2011

Rollinger, J.M.; Kirchmair, J.; Grienke, U.; Schuster, D.;  Liedl, K. R.; Schmidtke, M. (2011) Common cold and flu: Computational strategies for the identification of antiviral leads from nature. Invited lecture at the 2011 Spring ACS meeting, CINF division "Natural Products/Drug Discovery" in Anaheim, California, 28th March, 2011.

Rollinger. J.M. (2011) In silico prediction of bioactive phytochemicals: Expectations, realities and examples. Plenary lecture at the 5th International Conference on Polyphenols and Health, in Sitges/Barcelona, Spain, 19th October 2011.

Rollinger, J.M. (2011): Combination of ethnopharmacological knowhow with modern in silico tools. Plenary lecture at the 59th International Congress of the Society for Medicinal Plants and Natural Product Research in Antalya, Turkey, September 5th, 2011. Abstract: Planta Med. 77, 2011, L2, 1230.

Grienke, U.; Schmidtke, M.; Kirchmair, J.; Stuppner, H.; Liedl, K.R.; Rollinger J.M. (2010) Discovery of novel neuraminidase inhibiting scaffolds from Alpinia katsumadai. Oral presentation at the 58th International Congress of the Society for Medicinal Plants and Natural Product Research in Berlin, Germany, August 30, 2010. Abstract: Planta Med.76, 2010, SL-8, 1179.

Grienke, U.; Schmidtke, M.; Kirchmair, J.; Liedl, K.R.; Rollinger J.M. (2010) Identification of novel antiinfluenza constituents from Alpinia katsumadai. Oral presentation at the 2nd Life Science Meeting, Igls, Austria, 24.-25.09.2010.

Schmidtke, M.; Wutzler, P.; Rollinger, J. M. (2009) Target-based discovery of natural inhibitors to combat common cold and flu. Oral presentation at the International Workshop ‘Novel strategies to fight respiratory viral diseases’ in Berlin, Germany, 12-13. Oct. 2009.

Posters

Richter, M.; Walther, E.; Bohn, K.; Xu, Z.; Braun, H.; Grienke, U.; Rollinger, J.M.; von Grafenstein, S.; Liedl, K.R.; Kirchmair, J.; Sauerbrei, A.; Schmidtke, M. (2014): Reliability of different assays for identification of novel neuraminidase inhibitors (NAI). Poster presentation at the 24th Annual Meeting of the Society for Virology in Alpbach/Tyrol, Austria. March 26, 2014, P019.

Hoffmann, A.; von Grafenstein, S.; Kirchmair, J.; Liedl, K.R.; Rollinger, J.M.; Schade, D.; Sauerbrei, A.; Schmidtke, M. (2014): Analysis of recombinant influenza virus susceptibility to antiviral agents with respect to inhibitory mechanism studies. Poster presentation at the 24th Annual Meeting of the Society for Virology in Alpbach/Tyrol, Austria. March 26, 2014, P017.

Mair, C.E.; Grienke, U.; von Grafenstein, S.; Kirchmair, J.; Liedl, K.R.; Schmidtke, M.; Rollinger J.M. (2014): Reverse pharmacology: exploiting ethnopharmacological knowledge to identify antiviral agents against ARIs. Poster presentation at the 24th Annual Meeting of the Society for Virology in Alpbach/Tyrol, Austria. March 26, 2014, P008.

Walther, E.; Xu, Z.; Leitzinger, C.; Rollinger, J.M.; Grienke, U.; Kirchmair, J.; Liedl, K.R.; von Grafenstein, S.; Sauerbrei, A.; Pfister, W.; Schmidtke, M. (2013): Characterisation of pneumococcal neuraminidase (NA) and the effect of neuraminidase inhibitors (NAIs) on NA activity, bacterial growth, and biofilm formation. Poster presentation at the Joint Annual Meeting of the German Society for Hygiene and Microbiology (DGHM) and the German Society for Infectious Diseases (DGI) in Rostock, Germany. September 24, 2013, KMP02.

Grienke, U.; Richter, M.; Braun, H.; Kirchmair, J.; von Grafenstein, S.; Liedl, K.R.; Schmidtke, M.; Rollinger, J.M. (2013): New insights into the anti-influenza activity of licorice constituents. Poster presentation at the:

  • 61th International Congress of the Society for Medicinal Plant and Natural Product Research in Münster, Germany. September 3, 2013. Abstract: Planta Med. 79, 2013, PG3. DOI: 10.1055/s-0033-1352073
  • 5th Life Science Meeting and Annual Meeting of the Austrian Association of Molecular Life Sciences and Biotechnology (ÖGMBT) in Innsbruck, Austria. September 25, 2013, P74.

Mair, C.E.; Grienke, U.; von Grafenstein, S.; Kirchmair, J.; Liedl, K.R.; Schmidtke, M.; Rollinger, J.M. (2013): Bioprospecting diverse plant species for antiviral agents against upper respiratory tract infections. Poster presentation at the:

  • 61th International Congress of the Society for Medicinal Plant and Natural Product Research in Münster, Germany. September 4, 2013. Honoured with the Best Poster Award. Abstract: Planta Med. 79, 2013, PN57. DOI: 10.1055/s-0033-1352400
  • 5th Life Science Meeting and Annual Meeting of the Austrian Association of Molecular Life Sciences and Biotechnology (ÖGMBT) in Innsbruck, Austria. September 25, 2013, P73.

von Grafenstein, S.; Fuchs, J.E.; Huber, R.G.; Margreiter, M.A.; Mair, C.E.; Grienke, U.; Rollinger, J.M.; Kirchmair, J.; Schmidtke, M.; Liedl, K.R. (2013): Similarity in shape and electrostatics guide virtual screening for novel influenza nucleoprotein ligands. Poster presentation at the:

  • Gordon Research Conference – Computer Aided Drug Design in West Dover, VT, United States. July 24&25, 2013.
  • 5th Life Science Meeting and Annual Meeting of the Austrian Association of Molecular Life Sciences and Biotechnology (ÖGMBT) in Innsbruck, Austria. September 26, 2013, P174.

Kirchmair, J.; Rollinger, J. M.; Grienke, U.; Seidel, N.; Krumbholz, A.; Schmidtke, M.; Liedl, K. R. (2011) In silico identification of resistance-breaking inhibitors of influenza neuraminidase. Poster presentation at the 9th International Conference on Chemical Structures, Noordwijkerhout, The Netherlands, June 7, 2011.

Schmidtke, M.; Rollinger, J.M.; Grienke, U.; Seidel, N.; Krumbholz, A.; Wutzler, P.; Liedl, K.R.; Kirchmair, J. (2011) Discovery of novel natural neuraminidase inhibitors (NAI) based on in silico screening and antiviral investigations. Poster presentation at the 24th International Conference on Antiviral Research (ICAR) in Sofia, Bulgaria, May 9, 2011, P78.

von Grafenstein, S.; Wallnöfer, H.G.; Kirchmair, J.; Grienke, U.; Schmidtke, M.; Rollinger, J.M.; Liedl, K.R. (2011): Molecular dynamics simulations of neuraminidase - N1 subtype. Poster presentation at the:

  • 25th Molecular Modelling Workshop in Erlangen, Germany. April 4, 2011, P43.
  • 6th Meeting of Doctoral students from Innsbruck’s Medicinal University and of the Life Science Disciplines of the Leopold-Franzens-University Innsbruck in Innsbruck, Austria. November 24, 2010, P85.

von Grafenstein, S.; Wallnoefer, H.G.; Fuchs, J.E.; Huber, R.G.; Rollinger, J.M.; Kirchmair, J.; Liedl, K.R. (2011) Impact of tetramerization on neuraminidase dynamics and binding site conformations. Poster presentation at the Joint Meeting of the Austrian and German Pharmaceutical Societies, Innsbruck, 20.09.2011 - 23.09.2011