Chemoenzymatic route to macrocyclic hybrid peptide/polyketide-like molecules

Area of Science:

• Natural Product Biosynthesis
• Medicinal Chemistry
• Synthetic Biology

Background:

• Hybrid peptide-polyketides are crucial natural products with significant medical and biological importance.
• Their structural complexity and diversity arise from intricate biosynthetic pathways, often involving macrocyclization for bioactivity.

Purpose of the Study:

• To develop an efficient chemoenzymatic strategy for synthesizing diverse macrocyclic hybrid peptide-polyketides.
• To enable combinatorial library synthesis of these complex molecules for drug discovery.

Main Methods:

• Utilized Fmoc-protected epsilon-amino acid building blocks with embedded polyketide functionality.
• Employed combinatorial synthesis of linear precursors, activated as soluble thioesters or solid-phase tethered.
• Demonstrated macrocyclization using the TycC TE catalyst from a nonribosomal peptide synthetase.

Main Results:

• Successfully synthesized diverse linear precursors amenable to macrocyclization.
• Showcased the TycC TE catalyst's tolerance for a range of substrates.
• Established a versatile platform for accessing complex hybrid peptide-polyketide structures.

Conclusions:

• The chemoenzymatic strategy provides efficient access to stereochemically and functionally diverse macrocyclic hybrid natural products.
• This approach facilitates the generation of compound libraries for screening novel biological activities.
• The method holds promise for the discovery of improved or entirely new therapeutic agents.