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.
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.
The clinical trials will be performed in an area endemic for falciparum malaria. In a proof-of-principle study, 30 human patients will receive seven daily doses of 1 200 mg of fosmidomycin, and parasite counts will be performed every eight hours. To assess adverse events, evaluation of signs and symptoms, haematology, clinical blood chemistry and urine analyses will be performed. In a second study, groups of five patients will receive three daily doses of 400 mg fosmidomycin for five days. This dosage will be lowered consecutively until the cure rate is less than 100%. The third study will evaluate fosmidomycin as part of a combination therapy with already established antimalarial drugs, such as clindamycin. In parallel to the clinical evaluation of fosmidomycin, FR900098 and several pro-drugs of FR900098 with improved pharmacological profiles will be evaluated in monkeys in two separate pre-clinical studies against P. falciparum and P. cynomolgi, respectively. Groups will receive drugs at different dosages, and parasitaemia will be monitored daily by finger prick evaluation of Giemsa stained slides. To assess the potential development of resistance, the susceptibility of P. falciparum, field isolates from two different endemic areas will be measured in vitro, and the genes encoding DOXP reductoisomerase will be cloned from parasites with different levels of response to fosmidomycin and FR900098. Although the DOXP pathway of malaria parasites has been proven as a valid drug target, the events eventually leading to parasite death remain largely unknown. Therefore, tracing experiments with radioactive intermediates of the DOXP pathway will be carried out in order to analyse the incorporation of precursors into different isoprenoids.
Clinical proof-of-principle study, dose-finding study, and combination study
Data on antimalarial activity of further drug candidates in primate models.
In vitro activity of fosmidomycin and derivatives against P. falciparum field isolates.
DNA sequences of the target enzymes.
Identification of metabolites derived from the DOXP pathway.
New DOXP reductoisomerase inhibitors with improved antimalarial activity.
Jomaa Pharmaka Gmbh
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Tel: +49 64 1994 7528
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