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10.28.2015

artemisinin

The Nobel Assembly at Karolinska Institutet awarded the 2015 Nobel Prize in Physology & Medicine earlier this month. The honors went to the scientists who discovered artemisinin and avermectin, which respectively treat malaria and parasitic infections. We’ll explore ivermectin in another post, but today let’s talk artemisinin!

Chemistry of artemisinin

Artemisinin is a sesquiterpene lactone compound that contains an endoperoxide bridge – a functionality biochemists are unaccustomed to seeing, but is believed to be essential for the drug’s anti-malarial activity. The drug is the fastest treatment available for malaria cause by the parasite Plasmodium falciparum.

artemisinin

The structure of artemisinin. Note the lactone in the lower portion of the molecule above, and the peroxide bridge -O-O- in the top left portion.

Artemisinin is biosynthesized by the plant Artemisia annua,  or sweet wormwood. The plant is native to China and Vietnam, but is also grown in East Africa. When the plants reach full size after about 8 months of growth, the leaves are dried and then artemisinin is extracted by organic solvents, with hexane usually being the solvent of choice.

Artemisia annua, plant

Leaves of Artemisia annua.

Semi-synthetic pathways to artemisia also exist. Genetically engineered yeasts can produce artemisinic acid, a precursor to artemisinin. Artemisinic acid can then be purified and further modified synthetically to yield artemisinin. Scientists have also engineered tobacco plants to produce artemisinic acid.

Mechanism

How artemisinin works is hotly debated. The likeliest mechanism involves radical formation by the endoperoxide bridge. In this mechanism, iron from the heme in blood reduces the peroxide bond in artemisinin, producing an iron-oxo species. This iron-oxo species leads to to a series of reactions that generate radical oxygen species that kill the parasites causing malaria. Experiments show that exposure to artemisinin leads to damage in parasites’ vacuolar membranes, and that the compound is present in the Golgi, endoplasmic reticulum, and mitochondria of P. falciparum after exposure.

Discovery

In 1967, Tu Youyou led a Chinese research program to find a treatment for malaria as mandated by Chairman Mao.  After scouring the historic literature, for homeopathic and folk remedies to malaria symptoms, Tu Youyou stumbled across a recipe for extracting Artemisia annua in The Handbook of Prescriptions for Emergency Treatments written in 340 BC . After modernizing and improving the extraction prtocol,  Tu Youyou discovered the extract was indeed anti-malarial. And upon purification artemisinin, which is named qinghaosu in Chinese, was the compound responsible for its activity.  The results of his research were published in the Chinese Medical Journal in 1979.

So, that’s artemisinin in a nutshell. Artemisinin has saved countless lives world-wide. It is typically used in combination therapies these days. But even so, malaria still is estimated to kill over 1 million people each year.

12.13.2012

platelets confer resistance to parasites

Platelets prevent parasitic infestation. Image from Sciencemag.org

From Science magazine this week, a report on how platelets express genes to help kill parasites. An excerpt from the perspective:

The six Plasmodium parasite species that cause disease in humans (P. falciparum, P. vivax, P. malariae, P. ovale wallickerie, P. ovale curtisii, and P. knowlesi) appear to have independently colonized hominids and influenced the genetic composition of different human populations (3). For example, the genes responsible for sickle cell anemia, thalassemia, and glucose-6-phosphate dehydrogenase deficiency have a higher frequency in populations where malaria is, or was once, endemic. These genes provide protection against severe malaria syndromes and likely evolved in response to the disease by providing a survival advantage (4). Another of these genes encodes the Duffy-antigen receptor for chemokines (DARC/Fy glycoprotein/CD234) found on red blood cells. This protein also acts as a receptor for P. vivax (5), and human red blood cells lacking this receptor are resistant to invasion by this species and by P. knowlesi (6, 7). The impact of this genetic selection can be seen in the geographical distribution of P. vivax. This parasite is spread throughout tropical regions of the world, but is rare in large areas of central and western Africa where many individuals lack Duffy-antigen receptor expression on red blood cells. Thus, this “Duffy-negative” phenotype appears to have evolved as an innate resistance mechanism to P. vivax infection.

McMorran et al. extend previous work that demonstrated an important role for platelets in resistance to malaria (8) by identifying platelet factor 4 (PF4) as a key molecule in platelet-mediated killing of P. falciparum. PF4 is released from α granules in activated platelets to promote blood coagulation (9). It binds the Duffy-antigen receptor, along with several other chemokines (10). McMorran et al. found that a functional Duffy-antigen receptor is required for the antiparasitic activity of PF4.

Also check out the scientific research paper here [subscription required].

11.09.2012

malaria vaccine is a let down

A vaccine for malaria that was in clinical trials turns out not to produce robust effects. In a clinical trial only about 30% of study participants gained immunity as a result of the vaccine. From the NY Times:

Three shots of the vaccine, known as RTS, S or Mosquirix and produced by GlaxoSmithKline, gave babies fewer than 12 weeks old 31 percent protection against detectable malaria and 37 percent protection against severe malaria, according to an announcement by the company at a vaccines conference in Cape Town.

Last year, in a trial in children up to 17 months old, the same vaccine gave 55 percent protection against detectable malaria and 47 percent against severe malaria.

The new trial “is less than we’d hoped for,” Moncef Slaoui, Glaxo’s chairman of research and development said in a telephone interview. “But if a million babies were vaccinated, we would prevent 260,000 cases of malaria a year. This is a disease that kills 655,000 babies a year — 31 percent of that is a very large number.”

The company, which has already spent more than $300 million on the vaccine, wants to keep forging ahead, he said, “but it is not just our decision.”

The research was at least partially funded by the Bill & Melinda Gates Foundation.

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