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Plasmodium dUTPase


Malaria

Deoxyuridine Triphosphate Nucleotidohydrolase as a Drug Target against 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

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.

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