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New anti-inflammatory natural products from medicinal plants using inducible transcription factors and their signalling pathways as molecular targets

   
Project

QLK3-2000-00463

Cell factory area

3.3.4

EU Contribution

2 600 800 Euro

Duration

36 months

Type

Research project

Starting date

01-01-2001

Keywords
anti-inflamatory natural drugs
NF-kappaB inhibitory activity
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ABSTRACT
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The consortium assembled here will contribute to the development of new anti-inflammatory drugs for clinical use in the European Union and beyond by identifying medicinal plant extracts with NF-kappaB inhibitory activity and/or inhibitory effects on targets of the inflammatory cascade in periphearl and CNS tissues. These targets will include, for example, IL-1beta (IL-1B), TNFalpha (TNFa), prostaglandin E2 (PGE2), and IL-6. Subsequently, the compounds mediating this inhibitory effect will be isolated and their structure elucidated. The consortium has the capacity to evaluate the extracts in a large set of targets related to the transcriptional activation of gene products of relevance for inflammatory, inflammatory, immunomodulatory and apoptotic activity. Select compounds will be further studied in in vivo as well as in vitro systems and we expect that this research will form the basis for pre-clinical and clinical development.

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OBJECTIVES
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Main objective of the Consortium's porposed research co-operation is the identification of potent and specific modulators of NF-kappaB activation and of the signalling pathways involved in the inflammatory response of the body.

These modulators may serve as lead compounds for developing new pharmaceuticals to be used in the treatment of inflammatory diseases or conditions associated with an increased activity of the transcription factor NF-kappaB. Among the illnesses to be treated with such new pharmaceuticals are acute and chronic inflammatory diseases in peripheral tissue as well as conditions like stroke and Alzheimer's Disease.

Another goal is to contribute to the evaluation of European and non-European medicinal plants for use as novel therapeutics which constitutes an additional socio-economic value for the EU and its people.

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DESCRIPTION OF THE WORK
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The research project combines up-to-date ethnobotanical knowledge with modern molecular biology in order to identify potent inhibitors of the inducible transcription factor NF-kappaB, cyclooxygenases 1 and 2, and receptors and/or their ligands (peripheral TNFalpha, IL-6, PGE2, leukotriene B4 and IL-1B as well as PGE2, IL-6, TNFa and nitric oxide (NO) in the CNS).

The consortium's project is divide into two lines of investigation:

  • One line is looking at the mechanisms of inflammation in CNS tissues and the effects of established inhibitors. in vivo and in vitro models for CNS inflammation, brain infarction, brain trauma and Alzheimer's Disease will be established and transgenic rodents over-expressing NF-kappaB-regulated inflammatory enzymes (iNOS, PKC-delta) berdNovel biological targets involved in the kinase cascase related to NF-kappaB (especially novel RIP associated signalling proteins) will be identified.
  • The second line of research assesses plant extracts from >300 species for human monocytes [inhibition of COX activity/PGE2 release and synthesis of the cytokines IL-6, TNFa and IL-1B] and for their effect on apoptosis. Subsequent evaluation will lead to a better understanding of the mechanism(s)of action. Pure natural products responsible for this activity will be isolated and their structures elucidated. in vitro and in vivo evaluation of the most promising inhibitory compounds will combine both research streams: Compounds exhibiting 'in vitro activity' will be studied for their anti-inflammatory effects in the LPS-induced septic shock mouse model and the collagen-induced arthritis rodent model. In parallel, we will assess pre-tested compounds for anti-inflammatory activity on the newly identified targets in the CNS and in vivo models of stroke and Alzheimer's Disease.

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MILESTONES
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  • Milestone 1: Prioritisation of the species and the selection of samples (WP1).
  • Milestone 2: Identification of new targets in the RIP pathway (WP2) and the validating of the role of NF-kB-dependent and independent inflammation in common brain diseases (WP3).
  • Milestone 3: Selection of active plant samples based on the specificity and on the mechanism of action.
  • Milestone 4: Identification of novel inhibitors of NF-kB and of the inflammatory signalling pathway.
  • Milestone 5: Physiological and detailed biochemical characterisation of the novel NF-kB inhibitors and the ones of the inflammatory signalling pathway (this will be the basis for further drug development).

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DELIVERABLES
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Title Delivery date (month) Nature Dissemination level
D 1.1 Report on plants selected and active samples 21 R RE
D 1.2 Database summarising all relevant information (1 -) 21 O RE
D 1.3 Extracts for further study (1 -) 21 O CO
D 2.1 Report of all relevant data including sequence data, bioinformatics analysis (RIP) 28 R CO
D 2.2 Patent filing of novel RIP associated proteins 26 R PU
D 2.3 Establishment of targets used in WPs 3 and 4 7 (-15) O CO
D 3.1 Establishment of in vitro systems and Report on the role of NF-kB in animal/in vitro (neuronal models) 9-déc R CO
D 3.2 Establishment of in vivo systems for brain inflammation and report on the role of NF-kB in these systems 21 - (24) O CO
D 3.3 Establishment of transgenic animals 12 O CO
D 4.1 Prioritised plant samples with known mechanism (NF-kB inhibitors) 15 - (30) O CO
D 4.1 Patent filing of novel NF-kB inhibitors (standardised extracts) (susequently publications) 30 O PU
D 5.1 Prioritised plant samples with known mechanism (anti-inflammatory) 15 O CO
D 5.2 Patent filing of novel anti-inflammatories (standardised extracts) 15 O PU
D 6.1 Pure compounds with anti-inflammatory and/or NF-kB inhibitory activity (9) - 24 O CO
D 6.2 Report on the Results of WP6 24 R CO
D 6.3 Patents on pure (novel) compounds covering biological activities (and structure) (subsequently publications) (9) - 24 O PU
D 7.1 Pure compounds with known mechanism (NF-kB cascade inhibitors) 36 O CO
D 7.2 Patents on pure (novel) compounds covering biological activities (and structure) (subsequently publications) (21)-36 O PU
D 7.3 A report describing the molecular targets of the inhibitors of the NF-kB cascase (partner 8) 36 R CO
D 8.1 Pure compounds with known mechanism (anti-inflammatorics) 36 O CO
D 8.2 Patents on pure (novel) compounds covering biological activities (and structure) (subsequently publications) (21)-36 O PU
D 8.3 A report describing the molecular targets of the anti-infalmmatory compounds from plants selected for this project (partner 8) 36 R CO

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CONSORTIUM
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COORDINATOR
  Prof. Michael Heinrich
Centre for Pharmacognosy and Phytotherapy
The School of Pharmacy, University of London
29-39 Brunswick Square
WC1N 1AX London, United Kingdom
Tel: +44 2077535844
Fax: +44 2077535909
Michael.Heinrich@cua.ulsop.ac.uk

PARTNERS
  Dr. Bernd L. Fiebich
Neurochemistry Research Group
Universitätsklinikum Freiburg
Universitätsklinik für Psychiatrie und
Psychosomatik
Abteilung für Psychiatrie und Psychoterapie mit Poliklinik
Hauptstraße 5
79104 Freiburg, Germany
Tel: +49 7612706898
Fax: +49 7612706917
bernd_fiebich@psyallg.ukl.uni-freiburg.de

Prof. Jari Koistinaho
A.I. Virtanen Insitute for
Molecular Sciences
University of Kuopio
PO Box 1627
70211 Kuopio, Finland
Tel: +35 817163030
Fax: +35 817162427
koistina@messi.uku.fi

Prof. Dr. Yinon Ben-Neriah
Lautenberg Centre for Immunology
The Hebrew University
Hadassah Medical School
Jerusalem 91120, Israel
Tel: +972 26758718
Fax: +972 26424653
yinon@cc.huji.ac.il

PD. Dr. M. Lienhard Schmitz
Department of Immunochemistry (GO200)
German Cancer Research Centre (DKFZ)
INF 280
69120 Heidelberg, Germany
Tel: +49 6221423825
Fax: +49 6221423746
L.Schmitz@DKF2-Heidelberg.de

Prof. Dr. Giovanni Appendino
Department of Pharmaceutical Science
and Technology
University of Torino
Via Giuria 9
10125 Torino, Italy
Tel: +39 0116707684
Fax: +39 0116707687
appendin@pharm.unito.it

Prof. Dr. Eduardo Muñoz Blanco
Fisiología e Inmunología, Facultad de
Medicina, Universidad de Córdoba
Avda Menedez Pidal s/n
Cordoba, Spain
Tel: +34 957218267
Fax: +34 957218229
filmuble@uco.es

Drs Keith Ray, Melanie OP'Neill, and Jane Lewis
Glaxo Wellcome
(Compound Diversity Unit and Cell Biology Unit)
Glaxo Research and Development Ltd
Gunnels Wood Road
SG1 2NY Stevenage, United Kingdom
Tel: +44 1438764917
Fax: +44 1438764496
kpr0136@glaxowellcome.co.uk
(Keith Ray)

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