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SENSITIVE TARGETS
MALARIA, TUBERCULOSIS
Framework programme: 6
Call: 2
Project number:
LSHP-CT-2004-516017
EC contribution: € 1,000,000
Duration: 24 months
Type: STREP
Starting date: 1 January 2005
Graphic element Oxygen-Sensitive Enzymes of the Mevalonate-Independent Isoprenoid Biosynthesis Pathway as Targets for New Antimalarial and Anti-TB Drugs
Keywords: Tuberculosis; malaria; drug development; medicinal chemistry; screening; isoprenoid biosynthesis; iron-sulphur-cluster

Summary:

In plasmodium and mycobacterium, isoprenoids are synthesised by the mevalonate-independent 1-deoxy-D-xylulose 5-phosphate (DOXP) pathway which is absent in humans. The last two steps of the DOXP pathway are mediated by enzymes, which contain oxygen-sensitive iron-sulphur clusters and catalyse unique radical-type reactions. Using an advanced High Resolution Screening technology the project aims at the identification of lead inhibitors to be developed as novel drugs against malaria and tuberculosis.

Background:

Isoprenoids are essential for all organisms. In humans, isoprenoids are synthesised via the well-established mevalonate pathway. In most bacteria and some protozoal parasites, as well as in the plastids of plants, a completely unrelated biosynthetic route, the DOXP pathway, is used. Work on the DOXP pathway represents a relatively young field of research. In particular, any attempts to demonstrate the catalytic activity of some enzymes involved failed until very recently. This was mainly due to the fact that these enzymes are highly sensitive to oxygen.

Aim:

Since it is absent in humans, the DOXP pathway provides an attractive new drug target for the treatment of tuberculosis and malaria. It has already been shown in four clinical trials that fosmidomycin, an inhibitor of the DOXP pathway, is active against malaria. Therefore, the project aims at the development of inhibitors of additional targets within the DOXP pathway. As a long-term goal, the development of a synergistic drug combination inhibiting two enzymes of the DOXP pathway simultaneously is envisaged.

Expected results:

Within the project time, an oxygen-free screening technology will be established. It is expected that one or more lead inhibitors will be identified which can be developed through additional medicinal chemistry work into drug candidates.

Potential applications:

Principally, the project provides the potential to result in completely new drugs that could become a mainstay in anti-TB and anti-malaria therapy. These new drugs will be of particular importance to combat infections with pathogens resistant to conventional drugs.

Coordinator:

Hassan Jomaa
Justus-Liebig-Universit├Ąt Giessen
Biochemisches Institut
Friedrichstrasse 24
35392 Giessen
Germany
Tel: +49 641 99 47 558
Fax: +49 641 99 47 579
E-mail: hassan.jomaa@biochemie.med.uni-giessen.de

Partners:

Principal
Scientific
Participants
Official Address Other Information
2Hubertus IrthZernikepark 6-8
NL-9747 AN Groningen
The Netherlands
Tel: +31 50 547 42 70
Fax: +31 50 547 42 71
E-mail: info@kiadis.com
Website: http://www.kiadis.com/
3Serge Van CalenberghGhent University
Laboratorium voor Medicinale Chemie (FFW)
Harelbekestraat 72
BE-9000 Ghent
Belgium
Tel: +32 9 264 8124
Fax: +32 9 264 8146
E-mail: serge.vancalenbergh@ugent.be

 
 
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