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TRIoH
HIV/AIDS
Framework programme: 6
Call: 1
Project number:
LSHB-CT-2003-50348
EC contribution: € 11,610,500
Duration: 42 months
Type: IP
Starting date: 1 January 2004
Website: http://www.kuleuven.ac.be/molvirgen/projects/trioh/indextr.htm
Graphic element Targeting Replication and Integration of HIV
Keywords: HIV; AIDS; antiviral therapy; entry; reverse transcriptase; nucleocapsid; integrase; cellular co-factors; mechanism of action; resistance; chemistry; modelling; genomics; animal models

Summary:

Anti-HIV drugs, used at present in the clinic, target the viral reverse transcriptase (RT) or protease (PR). Combination therapies are the current standard of care. However, as a result of insufficient drug plasma levels or insufficient inhibitory power of the chosen drug combination, drug-resistant strains emerge, resulting in therapeutic failure. Consequently, there is a continuing need for new anti-HIV drugs to be used in combination with the current drugs, which should represent novel chemical entities targeting known targets (viral entry, reverse transcription), or should act on new viral targets of the HIV replication cycle (e.g. nucleocapsid, integrase) or interfere with cellular co-factors required for HIV replication.
TRIoH integrates different research efforts from different European partners on novel anti-HIV molecules targeting viral replication and integration. One main approach is multidisciplinary proteomics to study the basic science of HIV replication and integration, with special focus on the identification of new, cellular host factors. Our basic science, biotechnology and provocative chemistry will guide the development of new HIV therapeutics, leading to the development of new pre-clinical phase I compounds by our participating partners. Drug development will include all aspects of present day drug development: chemical synthesis, drug evaluation in enzymatic and cell culture assays, modelling and co-crystallisation, mechanism of action studies including biophysical measurements, antiviral resistance development and analysis, toxicological and pharmacological evaluation in cell culture and animal models.

Background:

The TRIoH consortium consists of HIV researchers that employ basic insight into the molecular virology of HIV and use advanced technologies of post-genomics, bio-informatics and biotechnology. These partners are experts in Europe to develop new technologies for accelerating anti-HIV drug development and novel anti-HIV drugs for the health of all people already infected with HIV or threatened to be infected in Europe and throughout the world, including people in developing countries.There is a close interaction between all involved scientific fields (chemistry, modelling, genomics, virology, structural biology, molecular biology, biochemistry, cell biology, biotechnology, pharmacology, toxicology) and our participating European research laboratories are integrated within these activities.

Aim:

The major goal of TRIoH is an integrated approach to develop novel, safe and more effective anti-HIV drugs ready for early clinical trials. Since the drugs we want to develop are targeting novel replication steps (nucleocapsid, integration, cellular factors) presently without drugs approved for clinical use, or new compounds against targets with approved drugs (entry, reverse transcriptase), the chance is high that novel chemical entities will be developed. Acceleration of development requires funding to bring together all required expertise (both technological and scientific) to establish a concerted anti-HIV drug development programme throughout Europe.

TRIoH will focus on the development of new anti-HIV leads, including the pre-clinical testing, and predicts to have at least one compound ready for clinical trials at the end of the project.

Expected results:

The research consortium will foster a technological platform of academic and industrial partners that will provide new targets and new assays, and will result in the development of new drugs.

Potential applications:

A. Impact on health problems and economic impact - AIDS as a major health problem

Since its discovery in the early 1980s, the spread of the acquired immune deficiency syndrome (AIDS) has taken pandemic proportions. At present, an estimated 40 million people are living with HIV/AIDS, and since the beginning of the epidemic 21.8 million individuals have died from the consequences of the immune deficiency. As a result, AIDS is one of the ten main causes of death in the world. The large majority of HIV-infected patients live in developing countries. There is a staggering prevalence in southern Africa. The impact of the AIDS epidemic affects socio-economic development of sub-Saharan Africa. These countries can hardly afford the currently used combination therapies so price arrangements with pharmaceutical companies are required.

But, also in Europe, AIDS remains an important health problem with new infections on the rise in many member states. The availability of potent combination cocktails and a decrease in the number of AIDS deaths may lead to neglect and an attitude of false security reflecting conquest of the disease in the West. The mistake of neglecting the development of new antibiotics two decades ago because of a false feeling of invincibility toward bacterial infections in the West, should not be repeated with AIDS. Because of antiviral resistance and toxicity problems of this life-long therapy, there is a continuous need to develop new drugs preferentially targeting new targets. Developing countries would also be helped by the development of antiviral drugs that are easy to administer in single dose regimens and cause no side effects. Europe can play an important role here to defend the rights of developing countries.

B. Critical mass and European dimension of TRIoH

It should be clear that our ambitious goals require IP-type funding (about € 12 million over three years) to cover the expenses of at least 27 different partners with different expertises who will each enrol between one and five scientists on the project. Moreover, expensive biotechnology and post-genomics (e.g. Fluorescence Correlation Spectroscopy, Mass Spectrometry) equipment and reagents, and expensive pre-clinical testing of lead compounds will have to be covered by IP funding. We believe that by funding AIDS research on drug development, targeting early replication and integration of HIV in Europe, Europe can re-enter the scientific and biotechnological stage as an important player in the AIDS-field, which is related to one of the most important health problems with an enormous socio-economic impact, but which is also an important market for biotech and pharma industry. Here again, Europe should show leadership in addressing at the same time an important societal health problem, a growing biotech and pharma market, and the problems associated with AIDS in developing countries and the availability of affordable drugs. Europe will fail to play this important role if it does not invest in HIV research.

Coordinator:

Myriam Witvrouw
Rega Institute for Medical Research
Virology and Chemotherapy
Katholieke Universiteit Leuven
Minderbroedersstraat 10
3000 Leuven
Belgium
Tel: +32 16 332170
Fax: +32 16 332131
Website: http://www.kuleuven.ac.be/molvirgen/

Partners:

Principal
Scientific
Participants
Official Address Other Information
2José A. EstéRetrovirology Laboratory IrsiCaixa
Hospital Universitari Germans Trias i Pujol
Trias I Pujol
ES- 08916 Badalona
Spain
Tel: +34 934 656 374
Fax: +34 934 653 968
E-mail: jaeste@ns.hugtip.scs.es
Website: http://www.irsicaixa.org
3Jean-Luc DarlixINSERM U. 567
Ecole Normale supérieure,
Virologie Humaine
Allée d’Italie 46
FR-69634 Cedex 07 Lyon
France
Tel: +33 4 72 72 81 69
Fax: +33 4 72 72 80 80
E-mail: jldarlix@ens-lyon.fr
Website:
http://www.ifr128.prd.fr/pageIFR128.htm
4Jaume VilarrasaStereoselective Synth. of Antibiotics & Antivirals
Dept. Química Orgànica,
Univ. Barcelona - Fac. Química
Av. Diagonal 647
ES-08028 Barcelona, Catalonia
Spain
Tel: +34 934 021 258
Fax: +34 933 397 878
E-mail: jvilarrasa@ub.edu
Website: http://www.ub.es
5Zeger DebyserLaboratory for Molecular Virology and Gene Therapy
KULAK and KULeuven
Minderbroedersstraat 10
BE-3000 Leuven
Belgium
Tel: +32 16 332183
Fax: +32 16 332131
E-mail:
zeger.debyser@med.kuleuven.ac.be
Website:
http://www.kuleuven.ac.be/molvirgen/
6Richard BenarousDepartment of Infectious Diseases
Institut Cochin
Hopital Cochin Batiment Gustave Roussy
Rue du Fg St-Jacques, 27
FR-75014 Paris
France
Tel: +33 1 40 51 65 71
Fax: +32 1 40 51 65 70
E-mail: benarous@cochin.inserm.fr
7Alba ChimirriUniversità di Messina
Dipartimento Farmaco-Chimico
C.da Annunziata
IT-98168 Messina
Italy
Tel: +39 09 06766412
Fax: +39 09 0355613
E-mail: chimirri@pharma.unime.it
Website: http://pharma.unime.it
8Ursula DietrichGeorg-Speyer-Haus Chemotherapeutisches Forschungsinstitut
Paul-Ehrlich-Strasse 42-44
DE-60596 Frankfurt-am-Main
Germany
Tel: +49 69 63395 216
Fax: +49 69 63395 297
E-mail:
ursula.dietrich@em.uni-frankfurt.de
Website: http://www.georg-speyer-haus.de
9Gilles DivitaCentre National de la recherche scientifique macromoléculaire (FRE 2593)
1919 route de Mende
FR-34293 Montpellier Cedex 5
France
Tel: +33 4 67 61 33 92
Fax: +33 4 67 52 15 59
E-mail: divita@crbm.cnrs-mop.fr
Website: http://www.crbm.cnrs.fr
10Joachim EngelsInstitut für Organische Chemie und
Chemische Biologie
Johann Wolfgang Goethe-Universität
Marie-Curie Straße 11
DE-60439 Frankfurt-am-Main
Germany
Tel: +49 69 / 798-29150
Fax: +49 69 / 798-29148
E-mail:
joachim.engels@chemie.uni-frankfurt.de
11Marina GottikhBelozersky Institute of Physico-Chemical Biology
Laboratory of Nucleic Acid Chemistry
119992 Leninskie gory, MSU
Moscow
Russia
Tel: +7095 939 54 07
Fax: +7095 939 31 81
E-mail: gottikh@belozersky.msu.ru
Website: http://www.belozersky.msu.ru
12Nicola M. HowarthDepartment of Chemistry,
Heriot-Watt University, Riccarton
UK-EH14 4AS Edinburgh
United Kingdom
Tel: +44 131 451 8026
Fax: +44 131 451 3180
E-mail: n.m.howarth@hw.ac.uk
Website: http://www.hw.ac.uk
13Robert KapteinBijvoet Center for Molecular Research
Utrecht University
Padualaan 8
NL-3584 CH Utrecht
The Netherlands
Tel: +31 30 2532652
Fax: +31 30 2537623
E-mail: kaptein@nmr.chem.uu.nl
Website:
http://www.bijvoet-center.nl/bijvoet
14Oliver T. KepplerUniversity of Heidelberg
Hygiene Institute, Faculty of Medicine, Department of Virology
Im Neuenheimer Feld 324
DE-69120 Heidelberg
Germany
Tel: +49 6221 565007
Fax: +49 6221 565003
E-mail:
oliver_keppler@med.uni-heidelberg.de
Website:
http://virology.hyg.uni-heidelberg.de/
15Lajos KovacsNucleic Acids Laboratory
Department of Medicinal Chemistry University
Dom ter 8.
HU-6720 Szeged
Hungary
Tel: +36 62 54 51 45
E-mail:
kovacs@ovrisc.mdche.u-szeged.hu
16Giovanni MagaDNA Enzymology and Molecular Virology
Istituto di Genetica Molecolare, IGM-CNR
via Abbiategrasso 207
IT-27100 Pavia
Italy
Tel: +39 03 8254 6354
Fax: +39 03 8242 2286
E-mail: maga@igm.cnr.it
Website: http://www.igm.cnr.it
17Silvio MassaUniversità degli Studi di Siena
Dip. Farmaco Chimico Tecnologico
Via Bianchi di Sotto 55
IT-53100 Siena
Italy
Tel: +39 0577 234332
Fax: +39 0577 234333
E-mail: massa@unisi.it
Website: http://www.unisi.it
18Yves MélyCNRS, Faculté de Pharmacie
Université Louis Pasteur
Laboratoire Pharmacologie et Physico-
chimie des Interactions Cellulaires
Route du Rhin 74
FR-67401 Illkirch
France
Tel: +33 3 90 24 42 63
Fax: +33 3 90 24 43 12
E-mail:
mely@aspirine.u-strasbg.fr
19Jean-François MouscadetCNRS UMR8113
École Normale Supérieure de Cachan, CNRS
61 Avenue du Président Wilson
FR-94235 Cachan Cedex
France
Tel: +33 1 47 40 76 75
Fax: +33 1 47 40 76 84
E-mail:
mouscadet@lbpa.
ens-cachan.fr

Website: http://www.ens-cachan.fr
20Tobias RestleUniversitätsklinikum Schleswig-Holstein
Campus Lübeck
Institut für Molekulare Medizin
Ratzeburger Allee 160
DE-23538 Lübeck
Germany
Tel: +49 451 500 2745
Fax: +49 451 500 2729
E-mail: restle@imm.uni-luebeck.de
21Inmaculada RobinaDepartamento de Química Orgánica
Facultad de Química,
Universidad de Sevilla
c/o García González, s/n
ES-41012 Seville
Spain
Tel: +34 954 557 150
Fax: +34 954 624 960
E-mail: robina@us.es
Website: http://www.us.es/quimica/
22Veljko VeljkovicCentre for Multidisciplinary Research
Institut of Nuclear Sciences VINCA
PO Box 522
11001 Belgrade
Yugoslavia
Tel: +381 11 453 686
Fax: +381 11 3440 100
E-mail: veljko01@hotmail.com
Website: http://www.vin.bg.ac.yu
23José VillalaínMolecular and Cellular Biology Institute
Campus de Elche,
Univ. Miguel Hernández
ES-03202 Elche-Alicante
Spain
Tel: +34 966 658 470
Fax: +34 966 658 758
E-mail: jvillalain@umh.es
Website: http://ibmc.umh.es
24Pierre VogelÉcole Polytechnique Fédérale de Lausanne
Institut de Chimie Moléculaire et Biologique, BCH-LGSA
CH-1015 Lausanne
Switzerland
Tel: +41 21 693 9371
Fax: +41 21 693 9375
E-mail: pierre.vogel@epfl.ch
Website:
http://isic.epfl.ch/vogel_e.htm
25Nils Gunnar JohanssonMEDIVIR AB
Lunastigen 7
SE-141 44 Huddinge
Sweden
Tel: +46 8 5468 3100
Fax: +46 8 5468 3199
E-mail: nils.gunnar. johansson@medivir.se
Website: http://www.medivir.se
26Donny StrosbergHybrigenics S.A.
3-5 impasse Reille
FR-75014 Paris
France
Tel: +33 1 58 10 38 00
Fax: +33 1 58 10 38 49
E-mail: adstrosberg@hybrigenics.com
Website: http://www.hybrigenics.com
27Johannes Petrus Maria LangedijkPepscan System B.V.
Edelherttweg 15
8203 AB Lelystad
Netherlands
Tel: +31 320 238515
Fax: +31 320 238120
E-mail: hans.langedijk@wur.nl
Website: http://www.pepscan.com

 
 
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