Biosynthesis-driven structure-activity relationship study of premonensin-derivatives

Area of Science:

• Natural product chemistry
• Drug discovery
• Biotechnology

Background:

• Controlled derivatization of natural products is crucial for drug discovery.
• Rapid generation of compound libraries is needed for structure-activity relationship (SAR) studies.
• Interference with the oncogenic KRas pathway is a key cancer research area.

Purpose of the Study:

• To generate a library of reduced polyketides using modified biosynthesis.
• To investigate the interaction of these polyketides with the KRas-interacting protein PDE6δ.
• To identify novel compounds for targeting the oncogenic KRas pathway.

Main Methods:

• Modified biosynthesis for polyketide library generation.
• Polyketide derivatization via side chain alteration.
• Manipulation of polyketide synthase for redox pattern and backbone length variation.
• Structural and biophysical analyses of polyketide-PDE6δ interactions.

Main Results:

• A library of reduced polyketides was successfully generated.
• The structural and biophysical basis for polyketide interaction with PDE6δ was elucidated.
• Non-natural polyketides with low nanomolar affinity to PDE6δ were identified.

Conclusions:

• Modified biosynthesis is an effective strategy for generating diverse polyketide libraries.
• Identified polyketides demonstrate high affinity for PDE6δ, suggesting therapeutic potential.
• These findings contribute to the development of novel KRas pathway inhibitors for cancer treatment.