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NEW ANTIMALARIALS


MALARIA

Clinical and Pre-Clinical Evaluation of Fosmidomycin and its Derivates as Antimalarial Drugs
Framework programme:
5
Project number:
ICA4-CT-2001-10078
EC contribution:
€ 1 799 948
Duration:
36 months
Type:
RS
Starting date:
1 January 2002

Summary:

The present project will help to develop fosmidomycin, an inhibitor of the DOXP reductoisomerase, into an antimalarial drug. In parallel to the clinical evaluation of fosmidomycin in human volunteers, tests with derivatives of fosmidomycin with demonstrably improved pharmacological profiles in two different non-human primate models will be the pre-requisite for a straightforward clinical development of a second generation of DOXP reductoisomerase inhibitors as antimalarial drugs. Furthermore, biochemical, molecular biological and pharmacological studies will increase our knowledge about the relevance of the DOXP pathway for the survival of malaria parasites, and demonstrate its potential as a new target for chemotherapy. Finally, new DOXP reductoisomerase inhibitors with improved antimalarial activity will be developed.

Objectives:

The early steps of isoprenoid biosynthesis were identified as valid targets for the therapy of malaria. Inhibitors of the DOXP reductoisomerase (fosmidomycin and FR900098) inhibit the in vitro growth of multidrug-resistant P. falciparum, and cure mice infected with the murine malaria parasite P. vinckei. The antimalarial efficacy of fosmidomycin in human patients will be demonstrated in a clinical phase II trial, alone and in combination with already established antimalarials. In addition, the antimalarial activity of improved fosmidomycin derivatives like FR900098 will be evaluated in monkeys. Studies will be performed on in vitro susceptibility of P. falciparum field isolates to fosmidomycin, on the genetic development of resistance. Additionally, new metabolites of the DOXP biosynthesis pathway will be identified.

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