Recent Advances in the Synthetic Biology of Natural Drugs

Abstract

Natural drugs have been transformed and optimized during the long process of evolution. These compounds play a very important role in the protection of human health and treatment of human diseases. Sustainable approaches to the generation of raw materials for pharmaceutical products have been extensively investigated in drug research and development because chemical synthesis is costly and generates pollution. The present review provides an overview of the recent advances in the synthetic biology of natural drugs. Particular attention is paid to the investigations of drugs that may be mass-produced by the pharmaceutical industry after optimization of the corresponding synthetic systems. The present review describes the reconstruction and optimization of biosynthetic pathways for nine drugs, including seven drugs from plant sources and two drugs from microbial sources, suggesting a new strategy for the large-scale preparation of some rare natural plant metabolites and highly bioactive microbial compounds. Some of the suggested synthetic methods remain in a preliminary exploration stage; however, a number of these methods demonstrated considerable application potential. The authors also discuss the advantages and disadvantages of the application of synthetic biology and various expression systems for heterologous expression of natural drugs. Thus, the present review provides a useful perspective for researchers attempting to use synthetic biology to produce natural drugs.

Keywords: biosynthesis; expression system; natural drugs; optimization; synthetic biology.

Figure 1

Some natural drugs studied by synthetic biology.

Figure 2

Optimization of the production of artemisinin. Blue route: By enhancing the expression of tHMGR and ERG20, together with ADS and CYP71AV1/CPR, the yields of amorpha-4,11-diene and artemisinic acid are 153 mg/L and more than100 mg/L, respectively; Pink route: After using S. cerevisiae CEN.PK2 as chassis and introducing a strong promoter (GAL₁ or GAL₁₀) before each gene (ERG10, ERG13, tHMG1, ERG12, ERG8, ERG19, IDI1, and ERG20), the yield of amorpha-4,11-diene reaches 40 g/L; Purple route: By enhancing expression two genes (ADH1 and ALDH1) and using the CTR3 promoter suppress expression of ERG9, the yield of artemisinic acid reached 25 g/L after optimizing fermentation conditions.

Figure 3

Optimization of the production of the paclitaxel precursors.

Figure 4

Production route for tanshinone precursors.

Figure 5

Production of thebaine in engineered yeast.