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<p>Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a promising source of new pharmaceuticals, yet the therapeutic potential of fungal RiPPs remains largely underexplored. Here we report asperigimycins as a distinct class of fungal RiPPs, featuring a unique heptacyclic scaffold consisting of a benzofuranoindoline core and three additional macrocycles, primarily assembled by six distinct fungi-specific DUF3328 oxidases. Inspired by the enhancement of anticancer activity through the N-terminal pyroglutamate in naturally occurring asperigimycins C and D, we chemically modify the inactive asperigimycin B with a series of lipid substitutions at its N-terminus. A derivative with a C-11 linear fatty acid, <b>2-L</b><sub><b>6</b></sub>, achieves nanomolar anticancer potency comparable to that of clinically approved antileukemia drugs. High-throughput CRISPR screening identifies the SLC46A3 transporter as a critical factor mediating <b>2-L</b><sub><b>6</b></sub> cellular uptake into human cells. Our findings highlight the promise of engineering asperigimycins as therapeutic leads for cancer treatment.</p><p></p>

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A class of benzofuranoindoline-bearing heptacyclic fungal RiPPs with anticancer activities

  • 期刊论文

  • 发表日期：

    2025年6月23日

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  • Qiuyue Nie,
  • Fanglong Zhao,
  • Xuerong Yu,
  • Mithun C. Madhusudhanan,
  • Caleb Chang,
  • Siting Li,
  • Sandipan Roy Chowdhury,
  • Bryce Kille,
  • Andy Xu,
  • Rory Sharkey,
  • Chunxiao Sun,
  • Hongzhi Zeng,
  • Shuai Liu,
  • Dishu Zhou,
  • Xin Yu,
  • Kevin Yang,
  • Sandra A. C. Figueiredo,
  • Maria Zotova,
  • Zichen Hu,
  • Alan Y. Du,
  • Dongyin Guan,
  • Rui Tang,
  • Todd Treangen,
  • Jin Wang,
  • Pedro N. Leão,
  • Yang Gao,
  • Junjie Chen,
  • Peng Liu,
  • Hans Renata,
  • Xue Gao

摘要

Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a promising source of new pharmaceuticals, yet the therapeutic potential of fungal RiPPs remains largely underexplored. Here we report asperigimycins as a distinct class of fungal RiPPs, featuring a unique heptacyclic scaffold consisting of a benzofuranoindoline core and three additional macrocycles, primarily assembled by six distinct fungi-specific DUF3328 oxidases. Inspired by the enhancement of anticancer activity through the N-terminal pyroglutamate in naturally occurring asperigimycins C and D, we chemically modify the inactive asperigimycin B with a series of lipid substitutions at its N-terminus. A derivative with a C-11 linear fatty acid, 2-L6, achieves nanomolar anticancer potency comparable to that of clinically approved antileukemia drugs. High-throughput CRISPR screening identifies the SLC46A3 transporter as a critical factor mediating 2-L6 cellular uptake into human cells. Our findings highlight the promise of engineering asperigimycins as therapeutic leads for cancer treatment.