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Plasmodium dUTPase
MALARIA
Framework programme: 6
Call: 4
Project number: LSHP-CT-2006-037587
EC contribution: € 2,079,016
Duration: 36 months
Type: STREP
Starting date: 1st January 2007
Graphic element Deoxyuridine Triphosphate Nucleotidohydrolase as a Drug Target against Malaria
Keywords: Malaria, Drug Discovery

Summary:

There are around 500 million clinical cases of malaria each year and about 1-2 million people die from this debilitating disease. There is an urgent need for the development of new drugs because of drug resistance issues. New drugs should have novel mechanisms of action to prevent cross-resistance with existing drugs. Some novel, drug-like and selective inhibitors of the enzyme, deoxyuridine triphosphate nucleotidohydrolase (dUTPase) from Plasmodium falciparum, the causative agent of malaria have been discovered. The role of this enzyme is to hydrolyse dUTP to dUMP, maintaining a low dUTP:dTTP ratio. The aim of this project is to optimise these early lead molecules to generate late-stage leads or preclinical drug candidates.

The project will include:

  1. Medicinal chemistry activities for the preparation and optimisation of lead compounds
  2. ADME-Tox assays to ensure that the compounds have correct “druglike” properties
  3. Biological evaluation to determine the efficacy of the compounds
  4. Mode of action studies
  5. Crystallography of inhibitors with the enzyme active site to assist in the drug design process.

Background:

As part of a Framework 5 programme (QLRT-2001-00305), the project team discovered a novel class of inhibitors, which selectively inhibit dUTPase form Plasmodium falciparum, the causative agent of malaria.

Aim:

The aim is to optimise these early lead molecules in order to generate advanced leads or preclinical drug candidates.

Expected results:

The expected results are compounds that are advanced leads or preclinical drug candidates for the treatment of malaria.

Potential applications:

The potential applications of outputs of this project are compounds, which could go through to preclinical development for the treatment of malaria and if successful proceed to clinical trials.

Coordinator:

Ian Gilbert
School of Life Sciences
University of Dundee
MSI/WTB/CIR Complex - Dow Street
Dundee DD1 5EH UK
Tel: +44 1382 731 438
Fax: +44 1382 386 373
E-mail: i.h.gilbert@dundee.ac.uk
Website: www.dundee.ac.uk

Partners:

Principal
Scientific
Participants
Official Address Other Information
2Nils Gunnar Johansson Medivir AB
Lunastigen 7
S-141 44 Huddinge
Sweden
Tel: +46 8 608 3100
Fax: +46 8 608 3199
Website: www.medivir.se
3Dolores González Pacanowska Instituto de Parasitología y Biomedicina "López-Neyra"
Consejo Superior de Investigaciones Científicas
Avda. del Conocimiento s/n
Parque Tecnológico de Ciencias de la Salud
18100 - Armilla - Granada
Spain
Tel: +34 958 181631/181621
Fax: +34 958 181633
Website: www.ipb.csic.es
4Keith Wilson Structure Biology Laboratory
Department of Chemistry
University of York
Heslington
York YO10 5YW
UK
Tel: +44 1904 328259
Fax: +44 1904 328266
E-mail: keith@ysbl.york.ac.uk
Website: www.york.ac.uk
5Reto Brun Swiss Tropical Institute
Parasite Chemotherapy
Socinstr. 57
P.O. Box
CH-4002 Basel
Switzerland
Tel: +41 61 284 82 31
Fax: +41 61 284 81 01
E-mail: Reto.brun@unibas.ch
Website: www.sti.ch

 
 
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