Download MendeleyNatural Product-Guided Discovery of a Fungal Chitinase Inhibitor.
Rush, C.L., Schuettelkopf, A.W., Hurtado-Guerrero, R., Blair, D.E., Ibrahim, A.F.M., Desvergnes, S., Eggleston, I.M., Van Aalten, D.M.F.(2010) Chem Biol 17: 1275
- PubMed: 21168763
- DOI: https://doi.org/10.1016/j.chembiol.2010.07.018
- Primary Citation of Related Structures:
2XUC, 2XVN, 2XVP - PubMed 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.
Organizational Affiliation:
Division of Molecular Microbiology, College of Life Sciences, University of Dundee, Dundee DD15EH, Scotland.
