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‘Pharaoh’s curse fungus’ turned into a cure for cancer
Natural products are critical for drug discovery and form a part of many FDA-approved small-molecule drugs. These drugs are vital for treating cancer, infectious diseases, and conditions affecting the cardiovascular, immune, and neurological systems. However, the emergence of drug resistance, low response rates, and the demand for targeted therapies highlight the necessity for novel natural compounds with unique structures and therapeutic potential. One such group of compounds are ribosomally synthesised and post-translationally modified peptides or, easier to remember, RiPPs.
RiPPs represent a key group of natural products distinguished by their chemical complexity and biological activity. All living kingdoms include this varied collection of natural products, which begin as precursor peptides made by ribosomes and undergo substantial enzyme modification to generate the final bioactive molecules. Primarily found in bacteria, RiPPs have also been identified in fungi, where they display a range of bioactivities such as antimitotic, phytotoxic, and nematocidal effects.
Asperigimycins
In their recent work, Nie and his colleagues analysed the presence of RiPPs-producing gene clusters in 12 different strains of Aspergillus, which could provide fungal RiPPs with excellent properties for further use. BGCs are groups of genes that are responsible for the synthesis of specialised metabolic compounds. Aspergillus BGCs produce a class of cyclic fungal RiPPs called asperigimycins. Among the 12 Aspergillus strains, the genome of Aspergillus flavus (AF) was eventually investigated for asperigimycins, based on the mass spectrometry data obtained after genetic analysis.
Four asperigimycins, namely asperigimycin A, B, C, and D, were purified from AF and characterised. The authors observed from the structural characterisation that any modifications to the asperigimycin gene could lead to the production of modified asperigimycin derivatives, thus producing new fungal RiPPs.
Antimicrobial and anticancer potency of asperigimycins
The authors evaluated the antimicrobial and anticancer efficiency of all four purified asperigimycins A-D. They observed that none of the asperigimycins exhibited antimicrobial activity against the gram-positive bacteria Bacillus subtilis and Staphylococcus aureus, the gram-negative bacteria Salmonella typhimurium and Escherichia coli and the yeast Candida albicans. Further, asperigimycins A and B also did not exhibit any anticancer activity against the leukaemia, liver, breast, or cervical cancer cell lines. However, to their surprise, they found out that asperigimycins C and D showed excellent cytotoxicity against a few leukaemia cancer cell lines. Asperigimycin D also demonstrated some potency against breast cancer cells (cell line MCF-7).
The reason for this difference in the anticancer potential of the asperigimycins was found in their structurally different N terminals, i.e., the starting point of the compound. While asperigimycins A and B had a free amine at their N-terminus, asperigimycins C and D had a cyclic pyroglutamate ring at their N-terminus. Thus, the authors hypothesised that the presence of the pyroglutamate provided asperigimycins C and D with cytotoxic activity against leukaemia cells, probably due to improved cellular permeability. The verification of their hypothesis has been discussed below.
Is it really the N-terminal?
To test their hypothesis, the authors substituted the free amine at the N-terminus of the inactive asperigimycin B (the most abundant compound obtained) with lipid chains (1-7 members) and an aromatic moiety. The addition of a 6-membered lipid chain to asperigimycin B provided it with significant cytotoxic potential against all the leukaemia and breast cancer cell lines tested. It was concluded that this activity was not only higher than that achieved by the asperigimycins C and D but also the commercial leukaemia drugs cytarabine and daunorubicin available in the market for the treatment of leukaemia. However, no anticancer activity of the modified asperigimycin B was observed against HepG2 or HeLa cells, indicating the selective nature of the asperigimycin.
Source: Created by the author on Canva
The researchers discovered that the cancer-killing effect of asperigimycins depended on how the compounds got into the cells. A specific transporter protein called SLC46A3 was responsible for moving a modified form of asperigimycin B into tiny compartments inside the cell, called lysosomes. This process, which relies on endocytosis (a way cells “swallow” substances), turned out to be crucial for the compound’s ability to fight cancer.
This research, therefore, is a step forward towards the advancement of drug development based on natural products. The possibility of structural modifications providing excellent functional properties to the compounds could pave the way for the synthesis of novel drugs derived from fungal RiPPs.
Link to the original post: Nie, Q., Zhao, F., Yu, X. et al. A class of benzofuranoindoline-bearing heptacyclic fungal RiPPs with anticancer activities. Nat Chem Biol (June 2025). https://doi.org/10.1038/s41589-025-01946-9.
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