Biocatalytic generation of bioactive biaryl natural products

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PROPOSAL SUMMARY Plants that produce biaryl natural products have a long history of medicinal use in naturopathic remedies due to the potent biological activities manifested by the biaryl architecture of these molecules. Over the last several decades, the biaryl scaffold has been widely acknowledged as a privileged structure in drug discovery; however, the full exploration of the medicinal properties and therapeutic development of natural products harboring biaryl scaffolds is hindered by the inability to isolate significant quantities of these compounds through natural sources or chemical synthesis. The potent biological activities of these natural products are contingent upon the axial chirality of the biaryl bond, yet forming a biaryl bond with this selectivity and precision remains a fundamental challenge in organic synthesis which has limited our access to these natural products. In contrast, Nature has evolved enzymes capable of forming these critical biaryl bonds with excellent selectivity. I aim to engineer these enzymes into robust biocatalysts capable of catalyzing the formation of axially chiral biaryl bonds with catalyst- controlled site-selectivity unmatched with conventional chemical methods. Through the directed evolution of these enzymes, I will synthesize biaryl natural products that have demonstrated potent and diverse biological activity, yet are currently understudied primarily due to their current inaccessibility. The two classes of biaryl natural products that I aim to access are biflavonoids and naphthylisoquinoline alkaloids. Both of these classes of natural products harbor the privileged axially chiral biaryl architecture and have demonstrated largely untapped therapeutic potentials. Most significantly, many biflavonoids exhibit anti-hepatitis B virus and anticancer activity and many naphthylisoquinoline alkaloids exhibit antimalarial and anti-HIV activity. Developing this biocatalytic platform will provide access to a library of these pharmacologically promising natural products and their derivatives, thereby accelerating their therapeutic development for applications including hepatitis B, cancer, malaria, and HIV/AIDS.