Natural Product-Guided Discovery of a Fungal Chitinase Inhibitor

C L Rush, A W Schuttelkopf, R Hurtado-Guerrero, D E Blair, A F M Ibrahim, Stephanie Desvergnes, Ian M Eggleston, D M F van Aalten

Research output: Contribution to journalArticle

23 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

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Chitinases
Biological Products
Aspergillus fumigatus
Machinery
Chitin
Aspergillus
Enzyme Inhibitors
Pathogens
Enzymes
Cell Division
Crystal structure
Cells
Derivatives
Atoms
Molecules
argifin
Substrates
Pharmaceutical Preparations

Cite this

Rush, C. L., Schuttelkopf, 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

Natural Product-Guided Discovery of a Fungal Chitinase Inhibitor. / Rush, C L; Schuttelkopf, A W; Hurtado-Guerrero, R; Blair, D E; Ibrahim, A F M; Desvergnes, Stephanie; Eggleston, Ian M; van Aalten, D M F.

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

Research output: Contribution to journalArticle

Rush, CL, Schuttelkopf, 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
Rush CL, Schuttelkopf 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
Rush, C L ; Schuttelkopf, A W ; Hurtado-Guerrero, R ; Blair, D E ; Ibrahim, A F M ; Desvergnes, Stephanie ; Eggleston, Ian M ; van Aalten, D 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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