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

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

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