Natural product-guided discovery of a fungal chitinase inhibitor.
Chem Biol
; 17(12): 1275-81, 2010 Dec 22.
Article
en En
| MEDLINE
| ID: mdl-21168763
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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Péptidos Cíclicos
/
Productos Biológicos
/
Quitinasas
/
Inhibidores Enzimáticos
Idioma:
En
Revista:
Chem Biol
Asunto de la revista:
BIOLOGIA
/
BIOQUIMICA
/
QUIMICA
Año:
2010
Tipo del documento:
Article
País de afiliación:
Reino Unido