title: Natural product-guided discovery of a fungal chitinase inhibitor.
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.
authors.affiliation: Division of Molecular Microbiology, College of Life Sciences, University of Dundee, Dundee DD15EH, Scotland.
authors.forename: Christina L
authors.initials: CL
authors.lastname: Rush
authors.forename: Alexander W
authors.initials: AW
authors.lastname: Schüttelkopf
authors.forename: Ramon
authors.initials: R
authors.lastname: Hurtado-Guerrero
authors.forename: David E
authors.initials: DE
authors.lastname: Blair
authors.forename: Adel F M
authors.initials: AF
authors.lastname: Ibrahim
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Desvergnes
authors.forename: Ian M
authors.initials: IM
authors.lastname: Eggleston
authors.forename: Daan M F
authors.initials: DM
authors.lastname: van Aalten
mesh_terms: D001232:Aspergillus fumigatus / Q000187:drug effects; D001665:Binding Sites; D001688:Biological Products / Q000737:chemistry* / Q000494:pharmacology; D020134:Catalytic Domain; D002688:Chitinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D005658:Fungi / Q000201:enzymology; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding
chemical_list: D001688:Biological Products; D004791:Enzyme Inhibitors; D010456:Peptides, Cyclic; C413566:argifin; D002688:Chitinases