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May 26, 2011

Background

According to a WHO report in 2006, half of the world's population is at risk of malaria, of which 250 million people are infected, and nearly 1 million of those die from the disease. Most of these deaths occur in children aged 5 or younger. Most cases of malaria occur in developing countries in low latitude regions. Malaria is a classic neglected disease and the epidemic areas are expected to spread more widely over the next few decades with the globalization of society.

Influenza-like symptoms (such as fever, headache, muscle pain, weakness, vomiting, or diarrhea) appear within 8 to 30 days after being infected with malaria. Thereafter, typical cyclic symptoms of malaria occur with fever, shaking chills, and excessive sweating, followed by brain damage caused by cerebral malaria or injury to vital organs, leading to death.

Currently, artemisinin-based combination therapy with kinin, chloroquine, pyrimethamine, or mefloquine is used to avoid drug resistance in the treatment of malaria. However, the appearance of drug-resistant Plasmodium falciparum is expected to be simply a matter of time. Thus, the development of novel anti-malarial drugs is an urgent issue.

Since countries in which malaria is epidemic are developing countries, a drug suited to such areas, namely an inexpensive and effective drug, is needed. Average treatment cost for 7 days necessary to save a life from malaria is 0.13, 0.14, and 2.68 U.S. dollars for chloroquine, sulphadoxine-pyrimethamine, and kinin, respectively. Because of the large infrastructure issues in African and other developing countries, the current reality is that these inexpensive drugs are not effectively and reliably delivered to areas where it is needed.

Technology development

Eisai identified GWT1 as a target molecule in development project for anti-fungal drug candidates, and found that the GWT1 protein is an enzyme which catalyzes acyl group transfer reaction, one of the glycosylphosphatidylinositol (GPI) biosynthesis pathways ^{1, 2)}, through joint research with National Institute of Advanced Industrial Science and Technology and Research Institute for Microbial Diseases, Osaka University.

GPI is known to play a key role in the growth and infectivity of protozoa. The cell surface of protozoa is covered with GPI-anchored proteins. Merozoite Surface Proteins (MSPs), the major surface proteins of Plasmodium falciparum, are essential for the growth of Plasmodium falciparum. GPI is abundantly expressed in Plasmodium falciparum as a glycolipid component of the cell membrane. It has become clear that GPI itself causes fatal symptoms as a toxin. Therefore, a compound that can selectively inhibit the biosynthesis of GPI, an essential component of Plasmodium falciparum growth as well as a toxin itself, has the potential to be developed as a very effective anti-malarial drug.

Eisai succeeded in isolating areas that we believe to be nearly the full-length of GWT1 homologues (PfGWT1) in Plasmodium falciparum through joint research with Research Institute for Microbial Diseases, Osaka University. Then, optimized PfGWT1 (oPfGWT1) by codon substitution was synthesized totally, which was expressed in yeast, resulting in confirmation of complementation activity for yeast GWT1 disruptant ³⁾. Evaluation of approximately 700 candidate compounds for anti-fungal drug using oPfGWT1 expressing yeast showed that a plurality of the compounds reduced the growth of oPfGWT1 expressing yeast at concentrations up to a few mg/ml. Some of these compounds did not reduce the growth of GWT1 expressing yeast in mice but reduced only the growth of oPfGWT1 expressing yeast, suggesting a potential for the generation of a selective malaria GWT1 inhibitor.

In vitro anti-P. falciparum activity was evaluated using a human erythroid culture system regarding initial candidate compounds for anti-fungal drug in a contract study by the Research Institute for Microbial Diseases, Osaka University. Results showed stronger antimalarial activity observed in a plurality of compounds, and in fact these compounds were identified as having anti-P. falciparum activity.

Drug discovery research for novel anti-malarial drugs was started in 2010 after acquiring in vitro and in vivo evaluation system technology using Plasmodium falciparum, from The Kitasato Institute.

Selected References

• 1)
  Tsukahara, K. et al. Mol. Microbiol. 48:1029-1042 (2003)
• 2)
  Umemura, M. et al. J. Biol. Chem. 278:23639-23647 (2003)
• 3)
  Hata, K et al. WO2004/048567 (2004)