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A Genomics-Based Approach Identifies a Thioviridamide-Like Compound with Selective Anticancer Activity.

Luca Frattaruolo1,2, Rodney Lacret1, Anna Rita Cappello2

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Researchers discovered new anticancer peptides, thioviridamide analogs, from bacteria. These novel ribosomally synthesized and post-translationally modified peptides (RiPPs) show potent cytotoxicity against cancer cells, offering new therapeutic potential.

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Area of Science:

  • Natural Product Chemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Thioviridamide, a novel ribosomally synthesized and post-translationally modified peptide (RiPP), exhibits potent anticancer activity.
  • Its unique thioamide-containing structure and biological promise warrant further investigation into related compounds.

Purpose of the Study:

  • To explore the structural diversity of thioviridamide-like natural products.
  • To characterize newly identified thioviridamide analogs and assess their biological activity.

Main Methods:

  • Bioinformatic analysis of bacterial genomes to identify thioviridamide-like pathways.
  • Isolation and characterization of natural products.
  • Transformation-associated recombination cloning and heterologous expression.
  • Cytotoxicity assays on cancer and noncancerous cell lines.

Main Results:

  • Three diverse thioviridamide-like compounds were isolated and characterized.
  • Heterologous expression of thiostreptamide S4 was achieved.
  • The unusual N-terminus of thioviridamide is an artifact of acetone extraction, not biosynthetic.
  • Thioalbamide demonstrated high cytotoxicity against cancer cells with lower toxicity to normal cells.

Conclusions:

  • The thioviridamide family of RiPPs is more diverse than previously known.
  • Thioalbamide represents a promising lead compound for anticancer drug development.
  • Understanding the post-translational modifications and extraction artifacts is crucial for characterizing RiPPs.