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ExCellENT-HIT
HIV/AIDS
Framework programme: 6
Call: 3
Project number: LSHP-CT-2006-037257
EC contribution: € 1,000,000
Duration: 24 Months
Type: STREP
Starting date: 1 November 2006
Graphic element Exploiting Cellular Transport of Nuclear Transcripts as HIV Innovative Therapy
Keywords: HIV, AIDS, antiviral therapy, reverse transcriptase, RNA helicase DDX3, cellular co-factors, viral RNA-transport, resistance, chemistry, modelling, genomics, andanimal models

Summary:

The objective of ExCellENT-HIT is the exploitation of the cellular pathways responsible for the nuclear export of unprocessed HIV-1 transcripts, as a novel anti-HIV therapeutic strategy. The approach is innovative; the objectives are very clear and focused and achievable within a two year period.

Combination therapies with drugs targeting viral proteins are the current standard of care for HIV-1 infections. However, drug resistant strains emerge, resulting in therapeutic failure. Consequently, new anti-HIV drugs are needed, which should represent novel chemical entities targeting new steps of the HIV replication cycle. Viruses need the host cellular metabolism in order to generate a progeny. By targeting cellular co-factors essential for HIV replication and whose inhibition is not harming the uninfected cells, drug resistance is less likely to occur.

Nuclear export of unspliced viral RNAs is an essential step of the HIV life cycle, regulated by the viral protein Rev.

Compelling experimental evidence recently identified the cellular DEAD-box RNA helicase DDX3 as an essential cofactor for viral mRNA export. Therefore, the consortium would seek to inhibit the nuclear export of unspliced viral RNAs activity by a two hit strategy targeting the cellular enzyme DDX3 and the viral protein Rev, thereby minimising the appearance of drug resistant HIV mutants. Basic science, biotechnology and provocative chemistry will integrate with the ultimate goal of targeting the Rev/DDX3 axis by the identification of molecular decoys that inhibit DDX3 helicase activity, Rev/DDX3 nuclear export and protein-protein interaction required for Rev/DDX3 function.

The knowledge and technology generated in this project on therapeutic targeting of nuclear export, protein-protein interaction and helicase activity is likely to cumulate in hit discovery and will have a wide applicability in the pharmaceutical industry.

Background:

The ExCellENT-HIT 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, modeling, genomics, virology, structural biology, molecular biology, biochemistry, cell biology, biotechnology, pharmacology, toxicology) and the related participating European research laboratories are integrated within these activities.

Aim:

The ever-expanding AIDS pandemic warrants development of new antiviral therapeutic strategies for the control of HIV replication. Since HIV replicates through an error prone reverse transcription step and because of the high intrinsic replication rate of the virus drug resistant strains frequently 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 ideally should represent novel chemical entities targeting steps of the HIV replication cycle which are still unexploited.

It has been shown that several cellular proteins are employed as essential cofactors by HIV.

The ExCellENT-HIT project is sharply focused on one step of the viral life cycle, namely the nuclear export of viral RNAs. This is a crucial step in HIV-1 replication, since the appropriate expression of viral genes paves the way to all the following steps like encapsidation, virion assembly and budding. Any drug targeting this step will act at an earlier level than protease inhibitors, shutting down viral proliferation at a step where no structural viral proteins (Gag-Pol, Env) or even full length genomic RNA have yet been produced in the infected cells. Therefore, the ExCellENT-HIT seeks to inhibit the nuclear export of unspliced viral RNAs activity by a “two hit strategy” targeting the cellular RNA helicase DDX3 and the viral protein Rev, thereby minimizing the appearance of drug resistance HIV mutants. ExCellENT-HIT will focus on the development of new anti-HIV leads, including the pre-clinical testing.

Expected results:

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

Potential applications:

  1. Impact on health problems and economic impact - AIDS as a major health problem
  2. 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 socioeconomic development of sub-Saharan Africa.

    These countries can hardly afford the currently used combination therapies so price arrangements with pharmaceutical companies are required. However, 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 theWest. 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.

  3. Critical mass and European dimension of ExcellENT-HIT
  4. It should be clear that the project's ambitious goals require IP-type (Innovation Programme) funding (about .1.2 million over two years) to cover the expenses of at the 5 different partners with different expertise who will each enrol between one and three 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.

    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 socioeconomic 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:

1 - Myriam Witvrouw
Division of Molecular Medicine
Department of Molecular and
Cellular Medicine/Faculty of Medicine
Kapucijnenvoer 33 VTCB+5
B-3000 Leuven,
Belgium
Tel: 32-16-332170
Fax 32-16-336336
E-mail: myriam.witvrouw@uz.kuleuven.be
Website: http://www.kuleuven.be/molvirgen/

Partners:

Principal
Scientific
Participants
Official Address Other Information
2Maurizio Botta Dip. Farmaco Chimico Tecnologico
Facult di Farmacia
Via Aldo Moro, snc
53100 Siena,
Italy
Tel 39-05-77234306
Fax 39-05-77234333
E-mail: botta@unisi.it
Website: www.unisi.it
3Zeger Debyser Division of Molecular Medicine
Department of Molecular and
Cellular Medicine/Faculty of Medicine
Kapucijnenvoer 33 VTCB+5
B-3000 Leuven,
Belgium
Tel:32-16-332183
Fax: 32-16-336336
E-mail:zeger.debyser@med.kuleuven.be
Website: http://www.kuleuven.be/molvirgen/
4Ursula Dietrich Applied Virology and Gene Therapy
Institute for Biomedical Research
Georg-Speyer-Haus
Paul-Ehrlich-Str. 42-44
60596 Frankfurt-am-Main,
Germany
Tel: 49-69-63395216
Fax: 49-69-63395297
Email: ursula.dietrich@em.uni-frankfurt.de
Website: www.georg-speyer-haus.de/ groups/gruppenpages/agdietrich/Index.htm
5Roland Stauber Regulation of Cell Growth,
Differentiation and Apoptosis
Institute for Biomedical Research
Georg-Speyer-Haus
Paul-Ehrlich-Str. 42-44
60596 Frankfurt-am-Main,
Germany
Tel: 49-69-63395216
Fax: 49-69-63395297
Email: ursula.dietrich@em.uni-frankfurt.de
Website: www.georg-speyer-haus.de/ groups/gruppenpages/agdietrich/Index.htm
6Oliver Keppler Department of Virology
Faculty of Medicine/Hygiene Institute
Im Neuenheimer Feld 324
69120 Heidelberg,
Germany
Tel: 49-6221-565007
Fax: 49-6221-565003
E-mail: oliver_keppler@med.uni-heidelberg.de
Website: www.klinikum.uni-heidelberg.de
7Giovanni Maga Instituto di Genetica Molecolare
IGM-CNR
Via Abbiategrasso 207,
27100 Pavia,
Italy
Tel: 39-0382-546335
Fax: 39-0382-422286
E-mail: maga@ipvgbe.igm.cnr.it
Website: www.igm.cnr.it/Maga/Magahomepage.html

 
 
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