Approaches and Recent Developments for the Commercial Production of Semi-synthetic Artemisinin

Abstract

The antimalarial drug artemisinin is a natural product produced by the plant Artemisia annua. Extracts of A. annua have been used in Chinese herbal medicine for over two millennia. Following the re-discovery of A. annua extract as an effective antimalarial, and the isolation and structural elucidation of artemisinin as the active agent, it was recommended as the first-line treatment for uncomplicated malaria in combination with another effective antimalarial drug (Artemisinin Combination Therapy) by the World Health Organization (WHO) in 2002. Following the WHO recommendation, the availability and price of artemisinin fluctuated greatly, ranging from supply shortfalls in some years to oversupply in others. To alleviate these supply and price issues, a second source of artemisinin was sought, resulting in an effort to produce artemisinic acid, a late-stage chemical precursor of artemisinin, by yeast fermentation, followed by chemical conversion to artemisinin (i.e., semi-synthesis). Engineering to enable production of artemisinic acid in yeast relied on the discovery of A. annua genes encoding artemisinic acid biosynthetic enzymes, and synthetic biology to engineer yeast metabolism. The progress of this effort, which resulted in semi-synthetic artemisinin entering commercial production in 2013, is reviewed with an emphasis on recent publications and opportunities for further development. Aspects of both the biology of artemisinin production in A. annua, and yeast strain engineering are discussed, as are recent developments in the chemical conversion of artemisinic acid to artemisinin.

Circulating Extracellular Vesicles Containing Xenobiotic Metabolizing CYP Enzymes and Their Potential Roles in Extrahepatic Cells Via Cell–Cell Interactions

“…Several CYPs and engineered variants are now used to synthesize and produce various compounds on a larger scale and for diverse purposes, including drug discovery and development [1]. For instance, artemisinic acid, a precursor for the Artemisia annua-derived antimalarial drug, artemisinin, has been synthesized using an engineered form of the plant's CYP71AV1 enzyme [103]. Furthermore, engineered CYPs have utility in statin synthesis.…”

P450 Monooxygenases Enable Rapid Late‐Stage Diversification of Natural Products via C−H Bond Activation

“…This question was answered with a second paper from the group, applying the method to the popular example of the anti‐malarial drug artemisinin ( 43 ) . P450 enzymes are involved in artemisinin's biosynthesis and thus semi‐synthetic supply is applicable,, which is managed through methods of metabolic engineering and synthetic biology ,. Late‐stage diversification of the drug can be achieved through synthetic chemistry tools used to synthesise new analogues or metabolic products,, often with aid of organometallic catalysis ,…”

Synthetic Biology - Mapping the Patent Landscape

“…However, in 2016 it was reported that Sanofi would not proceed with production and was selling its production facility [73]. At the time of writing recent reports suggest that production is under way and that more efficient routes to semi-synthetic synthesis have been identified [74].…”