Malarial drug target revealed
after scientists discovered the structure and function of the
malaria parasite, Plasmodium falciparum, for the first time. The
findings represent a breakthrough for future pharmaceutical
research.
Malaria causes more than 300 million acute illnesses and at least one million deaths annually. The disease is found throughout the tropical and sub-tropical regions of the world and research is set to aid in the development of drugs for one of the most severe and widely spread diseases in the world.
The research was carried out within the framework of a project (RAPID) at the Uppsala University Center for Structural Biology, Medical Chemistry, and Computer Chemistry. The results of which were published as an "accelerated publication" in the journal Biochemistry.
Using only computers, a research team at Uppsala University in Sweden has managed to map the amino acid sequence of the enzyme from the parasite. By comparing the enzyme's amino acid sequence with other known sequences, the team ran computer simulations of how it might move in order to find possible structures.
The team then looked at plausible combinations for how a substrate, a small peptide, might stick to the enzyme. In this way it was possible to predict the structure of the enzyme, how the substrate bonds, and the mechanism and rapidity of the chemical reaction. The fit with experimental data was good.
Professor Johan åqvist, lead researcher said: "The enzyme we studied is a new type, with previously unknown catalyst groups. This made it especially interesting as a target molecule for new drugs."
"Using only computer calculations, we succeeded in revealing both what it looks like and how it functions. It's the first time anybody ever did that."
The malaria parasite under study, Plasmodium falciparum, has several enzymes that directly attack haemoglobin in the blood when it invades. There is a tremendous interest in these enzymes among drug researchers. Today 1-3 million people die of malaria every year, and there is growing concern that the numbers will increase further.
Aqvist's research is especially important as the incidences of malaria continue to increase every year. More worryingly, Malaria parasites are developing unacceptable levels of resistance to one drug after another and many insecticides are no longer useful against mosquitoes transmitting the disease.
Vaccine research has produced few hopeful candidates and although scientists are redoubling the search, an effective vaccine is at best years away.
In a recent study, GlaxoSmithKline's RTS,S/AS02A malaria vaccine candidate protected a significant percentage of children against uncomplicated malaria, infection, and even severe forms of the disease for at least six months. This largest malaria vaccine efficacy trial ever conducted in Africa also re- confirmed the vaccine's safety in one- to four-year-old children.
The recombinant protein that fuses a part of the P. falciparum circumsporozoite (CS) protein with the hepatitis B surface antigen molecule, RTS,S, has been under development by GSK Biologicals for more than 15 years.
There are four types of human malaria Plasmodium vivax, P. malariae, P. ovale and P. falciparum. P. vivax and P. falciparum are the most common and falciparum the most deadly type of malaria infection. Plasmodium falciparum malaria is most common in Africa, south of the Sahara, accounting in large part for the extremely high mortality in this region. There are also worrying indications of the spread of P. falciparum malaria into new regions of the world and its reappearance in areas where it had been eliminated.
