TRIoH

HIV/AIDS

Targeting Replication and Integration of HIV

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

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.

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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:

Nº	Principal Scientific Participants	Official Address	Other Information
2	José A. Esté	Retrovirology 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
3	Jean-Luc Darlix	INSERM 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
4	Jaume Vilarrasa	Stereoselective 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
5	Zeger Debyser	Laboratory 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/
6	Richard Benarous	Department 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
7	Alba Chimirri	Università 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
8	Ursula Dietrich	Georg-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
9	Gilles Divita	Centre 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
10	Joachim Engels	Institut 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
11	Marina Gottikh	Belozersky 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
12	Nicola M. Howarth	Department 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
13	Robert Kaptein	Bijvoet 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
14	Oliver T. Keppler	University 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://www.klinikum.uni-heidelberg.de/Keppler.6552.0.html
15	Lajos Kovacs	Nucleic 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
16	Giovanni Maga	DNA 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
17	Silvio Massa	Università 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
18	Yves Mély	CNRS, 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
19	Jean-François Mouscadet	CNRS 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
20	Tobias Restle	Universitätsklinikum 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
21	Inmaculada Robina	Departamento 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
22	Veljko Veljkovic	Centre 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
23	José Villalaín	Molecular 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
24	Pierre Vogel	École 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
25	Nils Gunnar Johansson	MEDIVIR 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
26	Donny Strosberg	Hybrigenics 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
27	Johannes Petrus Maria Langedijk	Pepscan 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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