High throughput chemoenzymatic synthesis of antimalarial compounds

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PROJECT SUMMARY Malaria continues to pose a significant threat to human health with over 200 million cases each year and nearly 500,000 deaths worldwide. These staggering numbers illustrate the magnitude of this parasitic disease despite preventive programs such as insecticide-treated nets and available drugs. Thus, combatting this disease will require a multiprong approach that includes preventative measures such as vaccines and strategies to minimize transmission as well as effective treatments. Although recent advances in a malaria vaccine and social programs are poised for success, the efficacy of available small molecule drugs is threatened by the exponential rise in drug-resistance in Plasmodium falciparum (P. falciparum). For example, chloroquine resistance has steadily spread with the broad distribution of this drug first introduced in 1945 and resistance has already emerged toward artemisinin-based combination therapy (ACT) first administered in the mid-2000's. Based on this trajectory, there is a dire need for the development of novel small molecule antimalarial drugs. Historically, natural plant metabolites have provided the basis for potent antimalarial drugs. For example, quinine, the first antimalarial drug which is isolated from the bark of the Cinchona tree, provided the structural basis for the most widely used small molecule malaria treatment in history, chloroquine. Similarly, artemisinin is also a plant natural product, which has become the favored treatment for falciparum malaria and is often administered along with different classes of antimalarial drugs including mefloquine and amodiaquine. The complex structures of natural products, like artemisinin, can complicate or even completely derail the development of natural metabolites with promising antimalarial activity as therapeutic agents. This has left potent antiplasmodial natural products underexplored. For example, plant natural products, such as naphthylisoquinoline alkaloids and aryl anthraquninones, display potency against P. falciparum and selectivity for the parasite over human cell lines that exceeds chloroquine, yet restricted access to the natural compounds and synthetic analogs has limited the development of these compounds as medicines. To overcome the challenges associated with constructing complex biaryl natural products such as naphthylisoquinoline alkaloids and aryl anthraquinones through traditional synthesis, we propose a convergent chemoenzymatic approach toward this class of molecules. The biosynthetic pathways related to naphthylisoquinone and aryl anthraquinone plant metabolites have not been identified, therefore, we envision adapting enzymes associated with bacterial and fungal biosynthetic pathways for this purpose. We will employ a high throughput protein engineering strategy to tune and ensure access to enzymes with suitable substrate scope and desired site- and atroposelectivity. With the ability to rapidly generate targeted natural product classes and analogs thereof, we will be poised to interrogate the structural elements that contribute to their efficacy and optimized these compounds as next-generation antimalarial drugs.