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 journalArticle

    22 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

    Cite this

    Rush, C. L., Schuettelkopf, A. W., Hurtado-Guerrero, R., Blair, D. E., Ibrahim, A. F. M., Desvergnes, S., ... van Aalten, D. M. F. (2010). Natural product-guided discovery of a fungal chitinase inhibitor. Chemistry & Biology, 17(12), 1275-1281. https://doi.org/10.1016/j.chembiol.2010.07.018
    Rush, Christina L. ; Schuettelkopf, Alexander W. ; Hurtado-Guerrero, Ramon ; Blair, David E. ; Ibrahim, Adel F. M. ; Desvergnes, Stephanie ; Eggleston, Ian M. ; van Aalten, Daan M. F. / Natural product-guided discovery of a fungal chitinase inhibitor. In: Chemistry & Biology. 2010 ; Vol. 17, No. 12. pp. 1275-1281.
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    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.",
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    Rush, CL, Schuettelkopf, AW, Hurtado-Guerrero, R, Blair, DE, Ibrahim, AFM, Desvergnes, S, Eggleston, IM & van Aalten, DMF 2010, 'Natural product-guided discovery of a fungal chitinase inhibitor', Chemistry & Biology, vol. 17, no. 12, pp. 1275-1281. https://doi.org/10.1016/j.chembiol.2010.07.018

    Natural product-guided discovery of a fungal chitinase inhibitor. / Rush, Christina L.; Schuettelkopf, Alexander W.; Hurtado-Guerrero, Ramon; Blair, David E.; Ibrahim, Adel F. M.; Desvergnes, Stephanie; Eggleston, Ian M.; van Aalten, Daan M. F.

    In: Chemistry & Biology, Vol. 17, No. 12, 22.12.2010, p. 1275-1281.

    Research output: Contribution to journalArticle

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    AU - Schuettelkopf, Alexander W.

    AU - Hurtado-Guerrero, Ramon

    AU - Blair, David E.

    AU - Ibrahim, Adel F. M.

    AU - Desvergnes, Stephanie

    AU - Eggleston, Ian M.

    AU - van Aalten, Daan M. F.

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    KW - Aspergillus fumigatus

    KW - Cyclopentapeptide inhibitors

    KW - Saccharomyces cerevisiae

    KW - Molecular replacement

    KW - Family 18 chitinase

    KW - Allosamidin

    KW - Dissection

    KW - Disruption

    KW - Argifin

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    Rush CL, Schuettelkopf AW, Hurtado-Guerrero R, Blair DE, Ibrahim AFM, Desvergnes S et al. Natural product-guided discovery of a fungal chitinase inhibitor. Chemistry & Biology. 2010 Dec 22;17(12):1275-1281. https://doi.org/10.1016/j.chembiol.2010.07.018