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Chem Biol. 2010 Dec 22;17(12):1275-81. doi: 10.1016/j.chembiol.2010.07.018.

Natural product-guided discovery of a fungal chitinase inhibitor.

Author information

1
Division of Molecular Microbiology, College of Life Sciences, University of Dundee, Dundee DD15EH, Scotland.

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.

PMID:
21168763
PMCID:
PMC3518266
DOI:
10.1016/j.chembiol.2010.07.018
[Indexed for MEDLINE]
Free PMC Article

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