Reprogramming RiPP scaffolds through skeletal editing unlocks chemical space.

Area of Science:

• Chemical Synthesis
• Peptide Chemistry
• Biochemistry

Background:

• Biaryl-containing peptides, including RiPPs, show potent biological activities and high metabolic stability.
• The structural rigidity and strain in biaryl RiPPs have historically limited general synthetic accessibility.
• Developing versatile synthetic methods for these complex peptides is crucial for exploring their therapeutic potential.

Purpose of the Study:

• To establish a scalable and general synthetic strategy for producing RiPPs with Tyr-Trp cross-linkages.
• To comprehensively expand the chemical space of RiPPs through skeletal diversification.
• To synthesize novel RiPP scaffolds, including those with challenging quinazoline and quinoline motifs.

Main Methods:

• Employed modular synthetic strategies for constructing RiPPs.
• Utilized scaffold hopping for skeletal diversification of RiPPs.
• Developed a systematic and general approach for RiPP synthesis.

Main Results:

• Successfully synthesized a variety of RiPPs featuring Tyr-Trp cross-linkages.
• Demonstrated the high versatility of the modular synthetic approach.
• Achieved access to artificial RiPP scaffolds incorporating quinazoline and quinoline motifs via diversification.

Conclusions:

• The developed synthetic strategy is scalable, systematic, and general for RiPPs with Tyr-Trp cross-linkages.
• Skeletal diversification via scaffold hopping effectively expands the accessible chemical space of RiPPs.
• This work overcomes previous limitations in synthesizing complex RiPP scaffolds, opening new avenues for drug discovery.