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
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
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
Frankfurter. Strasse 50,
Tel: +49 64 1994 7528
Fax: +49 64 1994 7529
- Unité de Recherches, Hôpital Albert Schweitzer, Lambarene, Gabon
- Fundación Centro de Primates, Universidad Del Valle - Immunology Institute, Cali, Colombia
- Biomedical Primate Research Centre - Department of Parasitology, NL-Rijswijk, The Netherlands
- University of Strasbourg - Institute Of Bacteriology, FR-Strasbourg, France
- Organisation de Coordination pour la Lutte Contre les Endémies en Afrique Centrale - Laboratoire de Recherche sur le Paludisme/Oceac, Yaoundé, Cameroon
- Universidade de Sao Paulo - Departemento de Parasitologia, Instituto de Ciencias Biomedicas, Sao Paulo, Brazil