March
19,
2021
Utilizing Aromatic Prenyltransferases for the Late-Stage Modification of Natural Products
Natural products (NPs) harbor unique scaffolds not readily available through total synthesis, making them prime candidates for drug development. Prenylated NPs, in particular, display diverse biological activities, though little is known about how the prenyl substituents affect their activities. Furthermore, the alkylation of scaffolds with unnatural prenyl analogs opens previously unavailable chemical space ripe for drug development.
However, the complex structures of NPs often prevent functionalization through traditional means, leading us to focus initially on developing a chemoenzymatic methodology to overcome this limitation. We began by investigating the aromatic prenyltransferases (PTs), which have a natural proficiency for such reactions and utilize prenyl pyrophosphates as alkyl donors. Using a library of >60 synthetic alkyl pyrophosphates, we probed the substrate promiscuity of multiple PTs toward various alkyl groups, demonstrating the class’s promiscuity towards donors even in the presence of non-natural acceptors.
As a demonstration, this seminar will present the utility of CdpNPT in diversifying the antibiotic daptomycin. Alongside our extensive pyrophosphate library, CdpNPT generated daptomycin analogues with pendency against both susceptible and resistant strains of Gram-positive bacteria, thus validating the utility of our chemoenzymatic approach.
Additionally, the work also highlighted important hurdles to be addressed during platform optimization, namely the inefficient synthesis of alkyl pyrophosphates. Therefore, the latter portion of the seminar will address our efforts to develop a multienzyme platform for the synthesis and in-situ utilization of alkyl pyrophosphates.
Hosted by Professor Tim Bugni,
