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:

Partners:

Nº	Principal Scientific Participants	Official Address	Other Information
2	Nils 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
3	Dolores 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
4	Keith 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
5	Reto 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