Structure-Agnostic Bioactivity-Driven Combinatorial Biosynthesis Reveals New Antidiabetic and Anticancer...

Area of Science:

• Natural Product Chemistry
• Synthetic Biology
• Drug Discovery

Background:

• Combinatorial biosynthesis expands natural product diversity but is hindered by complex compound isolation and characterization.
• Analyzing metabolite bioactivity before isolation is crucial for efficient screening and optimization.

Purpose of the Study:

• To develop and demonstrate a structure-agnostic, bioactivity-driven workflow for combinatorial biosynthesis.
• To accelerate the identification of potent bioactive natural products, specifically triterpenoids targeting PTP1B.

Main Methods:

• Implemented an iterative combinatorial biosynthesis approach guided by bioactivity screening.
• Applied the workflow to generate triterpenoids and assess their inhibitory activity against PTP1B.

Main Results:

• Successfully narrowed down over 1000 potential combinations to five highly potent candidates using the bioactivity-guided workflow.
• Identified 20 diverse triterpenoids, including four novel compounds and a hybrid, as potent PTP1B inhibitors.

Conclusions:

• The bioactivity-driven workflow significantly expedites hit identification in combinatorial biosynthesis.
• This strategy is broadly applicable to discovering novel bioactive natural products for accelerated drug discovery.