ARCHIVED - Paving the way to a better malaria cure
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November 03, 2008— Saskatoon, Saskatchewan
The Chinese were onto something important thousands of years ago when they recorded their use of Artemisia annua to treat "hot and cold fevers," which probably included malaria. Today, researchers at the NRC Plant Biotechnology Institute (NRC-PBI) in Saskatoon are unravelling the mystery of how this common plant produces the compound artemisinin that can destroy Plasmodium, the parasite that causes malaria. Soon, we will be able to apply knowledge of Artemisia biochemistry and genetics to produce artemisinin inexpensively for use in antimalarial drugs. That's good news for the developing world where the disease kills more than a million people each year, and quinine and its derivatives — such as chloroquine — are no longer effective.
Dr. Patrick Covello, a senior NRC researcher at NRC-PBI, studies how plants produce substances that can be used for human health. "Artemisinin is the most important compound today in treating malaria, but only a few species produce it," he says. "If we can understand exactly how Artemisia annua makes it, we should be able to produce it more cheaply."
Several top research organizations began working on Artemisia annua when the World Health Organization recommended using artemisinin-based combination therapies instead of chloroquine to treat malaria. Unfortunately, the yield from Artemisia plants is low, making artemisinin relatively expensive to produce. Researchers are now pursuing avenues for creating larger supplies of artemisinin, either through genetically enhanced plants or the biosynthesis of the compound in microorganisms.
|NRC researchers Darwin Reed (left) and Dr. Pat Covello (right) discuss mass spectrometry results used to help identify Artemisia genes.|
An important advance occurred in 2006 when scientists at NRC and the University of California at Berkeley, working independently, cloned a gene involved in a key step in artemisinin biosynthesis. The Berkeley group used this gene to engineer baker's yeast to produce a precursor of artemisinin.
"NRC's contribution involves the isolation of all of the remaining genes that work sequentially in Artemisia annua, so they can be expressed in plants or microbes with a view to producing artemisinin," explains Dr. Covello. "By fully characterizing the biochemical pathway that plants use to produce artemisinin, we will pave the way towards inexpensive antimalarial drugs for the developing world."
Artemisia is a large, diverse genus of some 200-400 plant species, which include hardy herbs and shrubs known for their volatile oils. Common names of various species include wormwood, mugwort, sagebrush and tarragon. Artemisinin (from Chinese wormwood, Artemisia annua) is used to make one of the active ingredients in artemisinin-based combination therapies used to treat malaria.
In August 2008, Dr. Covello and his team, along with colleagues at the Flanders Institute for Biotechnology in Belgium, published a study in The Journal of Biological Chemistry. Using enzyme purification, mass spectrometry and molecular genetics, the team identified a gene involved in double bond reduction in a little understood part of the pathway — a finding that could prove seminal in efforts to artificially produce this compound. "The cloning and characterization of this particular enzyme presents some interesting biotechnical possibilities," says Dr. Covello. "We have a proof-of-concept for the microbial production of a compound called dihydroartemisinic acid that can be easily converted, chemically, to artemisinin."
NRC is pursuing applications for the Artemisia genes found. "We would like to see our findings put to good use on a non-profit basis," says Dr. Covello. "After all, too many people still die from malaria each year. That's a problem worth solving."
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