S78: Biosynthetic engineering approaches to natural product lead optimization

Polyketide natural products continue to represent excellent lead molecules for drug discovery and development. Biosynthetic engineering to optimise these polyketide lead molecules in a medicinal chemistry-type approach can generate novel analogues which may complement those accessible by semi-synthetic chemistry routes. A thorough understanding of the biosynthetic processes leading to the formation of a specific polyketide enables the development of focused libraries of closely related analogs through a combination of mutasynthetic and protein engineering approaches.  These analogs can be similar to the parent polyketide structure but display altered and sometimes unexpected biological profiles.  This lead optimization process will be illustrated using examples derived from a variety of polyketide biosynthetic pathways.