Language

English

Publication Date

12-1-2025

Journal

Nature Chemical Biology

DOI

10.1038/s41589-025-01946-9

PMID

40551021

PMCID

PMC13401907

PubMedCentral® Posted Date

7-27-2026

PubMedCentral® Full Text Version

Author MSS

Abstract

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.

Keywords

Humans, Antineoplastic Agents, Indoles, Cell Line, Tumor, Protein Processing, Post-Translational, Fungi, Peptides

Published Open-Access

yes

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