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Updated: May 5, 2026

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Engineering RiPP pathways: strategies for generating complex bioactive peptides.

Ayoola B Smith1, Renee C Ejindu1, Jonathan R Chekan1

  • 1Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, NC 27402, USA.

Trends in Biochemical Sciences
|May 7, 2025
PubMed
Summary

Ribosomally synthesized and post-translationally modified peptides (RiPPs) show promise as drug leads. Pathway engineering is crucial for overcoming limitations like poor bioavailability and enabling the development of novel therapeutic analogs.

Keywords:
RiPP biosynthesisRiPPspathway engineeringpeptide engineeringribosomally synthesized and post-translationally modified peptides

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Area of Science:

  • Natural Product Chemistry
  • Biotechnology
  • Drug Discovery

Background:

  • Natural products are vital sources of therapeutic agents.
  • Ribosomally synthesized and post-translationally modified peptides (RiPPs) offer biosynthetic plasticity and diverse scaffolds for drug discovery.
  • Many RiPPs exhibit poor bioavailability and proteolytic stability, hindering clinical applications.

Purpose of the Study:

  • To review recent advancements in overcoming challenges in RiPP pathway engineering.
  • To explore rational modifications of RiPP pathways for novel functions.
  • To derive new bioactive analogs with improved properties.

Main Methods:

  • Review of literature on RiPP biosynthesis and engineering.
  • Analysis of strategies for modifying RiPP precursor peptides and enzymes.
  • Examination of techniques for enhancing RiPP properties through pathway engineering.

Main Results:

  • Pathway engineering enables the creation of RiPP derivatives with potentially improved physicochemical properties.
  • Rational modification of RiPP pathways can lead to novel bioactive analogs.
  • Overcoming biosynthetic limitations is key to unlocking the therapeutic potential of RiPPs.

Conclusions:

  • Pathway engineering is essential for optimizing RiPPs for therapeutic use.
  • Strategic modifications of RiPP pathways can generate new drug candidates.
  • Further research in RiPP engineering holds promise for future drug development.