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, S., Eggleston, I. M. and van Aalten, D. M. F., 2010. Natural Product-Guided Discovery of a Fungal Chitinase Inhibitor. Chemistry & Biology, 17 (12), pp. 1275-1281.
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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.
|Creators||Rush, C. L., Schuttelkopf, A. W., Hurtado-Guerrero, R., Blair, D. E., Ibrahim, A. F. M., Desvergnes, S., Eggleston, I. M. and van Aalten, D. M. F.|
|Departments||Faculty of Science > Pharmacy & Pharmacology|
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