CONNECT: Synthesis of Highly Potent C-9 Artemisinin Derivatives for the Low-Cost Treatment of Artemisinin Resistant Malaria

Since its discovery from the extracts of sweet wormwood (Artemisia annua) in 1979. the anti-malarial drug artemisinin (3) is now the key starting material in the synthesis of life-saving artemisinin-based combination therapies (ACT). Yet. beginning in 2009. mutations in the parasites PfKelch13 protein began conferring artemisinin resistance in the Greater Mekong Subregion (GMS) (Figure 1).Since then. artemisinin resistance has been spreading and some ACT treatment failure rates have reached 26% to 46% in 2015. .An investigation done by the World Health Organization (WHO) found that the high cost of ACT therapy was causing affected countries and patients to prefer cheaper monotherapies or cause low ACT compliance. which fostered an ideal environment for parasite evolution. The high cost of ACT???s stems from the supply and cost of the primary starting material: artemisinin. which is still isolated from sweet wormwood. Efforts to reduce the cost and increase supply by using genetically engineered yeast also failed to lower the price.However. now that artemisinin resistance is spreading. lowering the cost of ACT???s alone will not stem the tide of resistance. New derivatives of artemisinin are needed that are both inexpensive and active against the resistant strains. Nevertheless. we believe these obstacles can be overcome. Given the combined expertise in synthetic chemistry and drug discovery. both UTSA and SwRI are now in a position to address this growing global crisis. We recently developed a new low-cost manufacturing technology to synthesize artemisinin (1) which utilizes amorpha-4.11-diene (AMD) (4). a biosynthetic precursor that can be made on large scale from genetically engineered yeast. We believe we can utilize this technology to intercept previously inaccessible highly potent artemisinin derivatives. based on strong preliminary data already obtained in both of our laboratories. These potent derivatives may circumvent the resistant malaria parasites evasion strategies at a cost no different than artemisinin (1) itself. We are eager to rapidly capitalize on our initial findings through support from the CONNECT Program to foster this already successful collaboration into a high impact. federally-funded research program for both institutions.