Natural product-guided discovery of a fungal chitinase inhibitor

Christina L. Rush, Alexander W. Schuettelkopf, Ramon Hurtado-Guerrero, David E. Blair, Adel F. M. Ibrahim, Stephanie Desvergnes, Ian M. Eggleston, Daan M. F. van Aalten

    Research output: Contribution to journalArticlepeer-review

    27 Citations (Scopus)

    Abstract

    Natural products are often large, synthetically intractable molecules, yet frequently offer surprising inroads into previously unexplored chemical space for enzyme inhibitors. Argifin is a cyclic pentapeptide that was originally isolated as a fungal natural product. It competitively inhibits family 18 chitinases by mimicking the chitooligosaccharide substrate of these enzymes. Interestingly, argifin is a nanomolar inhibitor of the bacterial-type subfamily of fungal chitinases that possess an extensive chitin-binding groove, but does not inhibit the much smaller, plant-type enzymes from the same family that are involved in fungal cell division and are thought to be potential drug targets. Here we show that a small, highly efficient, argifin-derived, nine-atom fragment is a micromolar inhibitor of the plant-type chitinase ChiA1 from the opportunistic pathogen Aspergillus fumigatus. Evaluation of the binding mode with the first crystal structure of an A. fumigatus plant-type chitinase reveals that the compound binds the catalytic machinery in the same manner as observed for argifin with the bacterial-type chitinases. The structure of the complex was used to guide synthesis of derivatives to explore a pocket near the catalytic machinery. This work provides synthetically tractable plant-type family 18 chitinase inhibitors from the repurposing of a natural product.

    Original languageEnglish
    Pages (from-to)1275-1281
    Number of pages7
    JournalChemistry & Biology
    Volume17
    Issue number12
    DOIs
    Publication statusPublished - 22 Dec 2010

    Keywords

    • Screening-based discovery
    • Aspergillus fumigatus
    • Cyclopentapeptide inhibitors
    • Saccharomyces cerevisiae
    • Molecular replacement
    • Family 18 chitinase
    • Allosamidin
    • Dissection
    • Disruption
    • Argifin

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