Molecular Farming in Artemisia annua, a Promising Approach to Improve Anti-malarial Drug Production

Abstract

Malaria is a parasite infection affecting millions of people worldwide. Even though progress has been made in prevention and treatment of the disease; an estimated 214 million cases of malaria occurred in 2015, resulting in 438,000 estimated deaths; most of them occurring in Africa among children under the age of five. This article aims to review the epidemiology, future risk factors and current treatments of malaria, with particular focus on the promising potential of molecular farming that uses metabolic engineering in plants as an effective anti-malarial solution. Malaria represents an example of how a health problem may, on one hand, influence the proper development of a country, due to its burden of the disease. On the other hand, it constitutes an opportunity for lucrative business of diverse stakeholders. In contrast, plant biofarming is proposed here as a sustainable, promising, alternative for the production, not only of natural herbal repellents for malaria prevention but also for the production of sustainable anti-malarial drugs, like artemisinin (AN), used for primary parasite infection treatments. AN, a sesquiterpene lactone, is a natural anti-malarial compound that can be found in Artemisia annua. However, the low concentration of AN in the plant makes this molecule relatively expensive and difficult to produce in order to meet the current worldwide demand of Artemisinin Combination Therapies (ACTs), especially for economically disadvantaged people in developing countries. The biosynthetic pathway of AN, a process that takes place only in glandular secretory trichomes of A. annua, is relatively well elucidated. Significant efforts have been made using plant genetic engineering to increase production of this compound. These include diverse genetic manipulation approaches, such as studies on diverse transcription factors which have been shown to regulate the AN genetic pathway and other biological processes. Results look promising; however, further efforts should be addressed toward optimization of the most cost-effective biofarming approaches for synthesis and production of medicines against the malaria parasite.

A Systematic Review of Anti-malarial Properties, Immunosuppressive Properties, Anti-inflammatory Properties, and Anti-cancer Properties of Artemisia Annua

“…The results showed that AaWRKY1 increased the artemisinin content through ADS and CYP regulation (27). As far as AN molecule in Artemisia is in low concentration, it is quite expensive, and different genetic manipulation approaches are difficult to do; thus, regulation of AN genetic pathway and other biological processes is costly (28). Artemisinin and total flavonoids levels were higher in samples obtained from high land areas (western and south western region) compared to those obtained from lowland regions.…”

Markers of oxidative‐nitrosative stress induced by artesunate are followed by clastogenic and aneugenic effects and apoptosis in human lymphocytes

“…Artesunate (ARS) is a semi‐synthetic derivative of artemisinin, a sesquiterpene lactone compound that is naturally produced by Artemisia annua L. (Pulice, Pelaz, & Matías‐hernández, ; Zuo, Li, Liu, Feng, & Chen, ). Over the past several years, ARS has been used as an outstanding antimalarial drug, and an increasing number of further pharmacological actions have been reported (Noubiap, ).…”

Successes of artemisinin elicitation in low-artemisinin producing Artemisia annua cell cultures constrained by repression of biosynthetic genes

“…Given the economic importance of artemisinin, the sole dependency on plant-based production periodically fails to meet the global demand due to irregular agricultural supply, which then renders fluctuations in the market and reductions in artemisinin inventory [9, 10]. To mitigate supply uncertainties and price volatility, biotechnological alternatives such as genetic modification, crop breeding and semi-synthetic production were considered with the latter far more successful [11]. The semi-synthesis approach has the production capacity to yield approximately 60 tonnes of artemisinin annually, but it also involves the trade-off between efficiency and profitability.…”

“…Naturally, artemisinin biosynthesis occurs in glandular secretory trichomes that are present on foliage, stems and inflorescences of the A. annua plant [15, 16]. Due to its compartmentalized synthesis and influence by physiological, seasonal and environmental factors, artemisinin concentration is highly variable with reported values of 0.1 – 10 mg g -1 dry weight (DW) [11, 17]. With the biosynthetic pathway of artemisinin formation fully elucidated over the past decade, it was learnt that within the species A. annua two contrasting chemotypes can be distinguished, which are characterized by the differing contents of artemisinin and its precursor (Fig 1).…”