Microbial Synthesis of Novel Terpenoid-Based Inhibitors

Terpenoids represent an important, pharmaceutically relevant class of natural products; unfortunately, their low natural abundance and pronounced chemical complexity often hinder their development into drugs. In this talk, we introduce an approach for building terpenoid-based inhibitors, or “leads”, that can be readily synthesized in microbial hosts. Starting with a simple diterpenoid pathway, we use directed evolution to build inhibitors of an enzyme implicated in diabetes. The resulting platform, which accommodates thermodynamic, enzymological, and metabolic considerations, addresses two problems often examined separately—the discovery of natural-product based leads and the synthesis of those leads—by supplying an approach to lead discovery in which microbial “synthesizability” is a search constraint.