University of Oklahoma
Utilizing aromatic prenyltransferases for the late-stage modification of natural products
The development of new drug candidates is currently limited by insufficient access to complex molecules with novel functionality. Natural products (NPs) offer a solution to this problem by providing unique structural scaffolds not readily envisioned or available by total synthesis, making them prime candidates for drug development. Prenylated NPs, in particular, display a diverse spectrum of biological activities (anti-inflammatory, antibacterial, anticancer, antiviral), but little is known about how the prenyl/alkyl substituents affect the compounds’ corresponding activities. Furthermore, alkylation of existing scaffolds with unnatural prenyl analogs opens a previously unavailable chemical space with the potential to spawn new drug leads. The complex structures of NPs often prevent efficient functionalization through traditional means, so the focus of our initial research was developing a chemoenzymatic methodology for the late-stage diversification of bioactive NPs.
We began by investigating the aromatic prenyltransferases (PTs), an enzyme class with a natural proficiency for these reactions that use prenyl pyrophosphates as alkyl donors. Using a vast library of synthetic pyrophosphates (>60 compounds), we probed the substrate promiscuity of multiple PTs toward different alkyl groups.