Malaria cornered
a group of British biochemists have discovered a cavity in the molecular structure of an enzyme, essential to the malarial parasite, which could act as a docking point for tailor-made drugs designed to inactivate the enzyme and disable the parasite.
The most deadly parasitic protozoan Plasmodum falciparum , which kills more than a million people every year, is rapidly becoming resistant to drugs. So biologists are searching for a new cure that will cripple the parasite without harming the human host. This calls for knowing the structure of the protein to be targeted. Leo Brady of the University of Bristol, uk, examined a parasite's protein enzymes, lactate dehydro-genase (ldh) (New Scientist, Vol 152, No 2056).
Brady says that this enzyme may be the perfect target for the drug as all organisms use ldh to digest sugars. His team used x-ray crystallography to determine the three-dimensional structure of this ldh to find a cleft, ten atoms long, five atoms wide and eight atoms deep next to its catalytic centre. The next step is to design chemicals that fit into the eight atom deep depression and block the catalytic centre.
"For drug design this is perfect,'says Brady. "It is next to the active site of the enzyme and unique to the parasite.' Human ldh has no cleft so it is supposed that the drug will leave it unharmed. The finding explains the partial success of one known inactivator of P falciparum ldh, the researchers say. Gossypol, a chemical from cottonseed oil, inhibits the parasite's ldh 40 times as strongly as it inhibits human ldh. Up to now, no one understood the reason.
Brady says computer models suggest that gossypol uses the cavity to attach itself more strongly to the malarial enzyme. Chemists may now be able to change the shape of gossypol to fit the cavity better. This could enable it to inhibit the parasite's ldh even more strongly, and could even make it powerful enough to use as an antimalarial drug.
Ed Nuzum, who studies experimental malarial therapies at the Walter Reed Army Institute of Research in Washington dc, said: "What they have done so far is great.' But he adds that ldh inhibitors which work in the test tube may not necessarily kill the parasite inside cells. Nuzum adds, "Until we test a new drug, we never know if malaria has a way to circumvent it.'