BLI Research Project By: Tiffany Hou Artemisinin

Introduction Malaria affects hundreds of thousands of people each year in the tropics and sub tropics Many anti-malarial drugs have developed resistance ACTs are the best form of treatment, but is largely unaffordable Scientists are trying to use synthetic biology to produce ACTs

Malaria About half of the world is at risk for malaria 219 million people are infected with malaria every year and 660,000 die from it

How Does Malaria Attack the Body?

Artemisinin Powerful anti-malarial drug Derived from Artemisia annua (A. annua) Grows in China and Vietnam First synthesized in 1979 by Chinese scientists Artemisinin is part of the isoprenoid family, which are organic compounds composed of two or more units of hydrocarbons

How Does Artemisinin Work? Reduces parasite’s biomass Attacks the parasite’s sexual stage of life cycle Main chemical feature is the unstable bond between two oxygen atoms which allows it to produce free radicals that break up proteins in the protozoa The release occurs upon exposure to Hemozoin

Problems and Limitations of Artemisinin Cost Poor cure rate of monotherapy Neurotoxicity

Cost Artemisinin has presented a supply chain challenge in the pharmaceutical industry The demand has outstripped the supply and the shortages have caused the prices to soar A dose of Artemisinin costs $1.30 whereas another anti- malarial drug, chloroquine, costs $0.25 per dose

Poor Cure Rate of Monotherapy Modeling studies suggests 6 days of treatment, but high rates of recrudescence do not match up with the model High rates are usually attributed to the short half life of artemisinin and the increased drug clearance caused by repeated dosage Pharmacokinetic behavior is not the only problem

Neurotoxicity Artemisinin has been show to cause brainstem toxicity in animals in pre-clinical experiments Millions of doses in various formulations have been given to humans and none of them show signs of major neurotoxicity Probable cause of neurotoxicity is the duration of exposure rather than maximum concentrations There has been a recent claim that artemisinin causes mild but significant hearing loss Concern of neurotoxicity should be maintained in children who have a more vulnerable neurological system and have limited therapeutic experience

The Heroes Jay Keasling Amyris and Sanofi World Health Organization

Derivatives and ACTs Artemisinin derivatives are semi-synthetic artemisinin based compounds that improve the effectiveness of artemisinin ACTs are Artemisinin-based Combination Therapy treatments which are made from fast acting artemisinin based compounds and drugs from a different class Benefits of ACTs are their high efficacy, fast action, and the reduced likelihood of resistance formation

Microbial Production of Artemisinin

How Does Microbial Production of Artemisinin Solve the Problem? Cost is lowered because extracting artemisinin from the plant is much more difficult and time consuming Access of the technology to produce synthetic artemisinin can be restricted to responsible manufacturers who will only manufacture and sell ACTs Not much is known about the link between artemisinin and neurotoxicity, but artemisinin derivatives have less major toxicity than other available anti-malarial drugs

Other Benefits Synthetic artemisinin is anticipated to have an impact on the pervasiveness of counterfeit drugs

Work Cited