Abstract
A 384-well microtitre plate fluorescence cleavage assay was developed to identify inhibitors of the cysteine protease falcipain-2, an important antimalarial drug target. Bioassay-guided isolation of a MeOH extract from a myxobacterium Chitinophaga sp. Y23 isolated from soil collected in Singapore, led to the identification of a new acyltetrapeptide, falcitidin (1), which displayed an IC 50 value of 6 μM against falcipain-2. The planar structure of 1 was secured by NMR and MS/MS analysis. Attempts to isolate further material for biological testing were hampered by inconsistent production and by a low yield (<100 μg l -1). The absolute configuration of 1 was determined by Marfey's analysis and the structure was confirmed through total synthesis as isovaleric acid-D-His-L-Ile-L-Val-L-Pro-NH 2. Falcitidin (1) is the first member of a new class of falcipain-2 inhibitors and, unlike other peptide-based inhibitors, does not contain reactive groups that irreversibly bind to active cysteine sites.
Original language | English |
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Pages (from-to) | 259-264 |
Number of pages | 6 |
Journal | Journal of Antibiotics |
Volume | 66 |
Issue number | 5 |
DOIs | |
Publication status | Published - 2013 May |
Keywords
- Chitinophaga
- Falcipain
- Falcitidin
- Malaria
- Myxobacteria
- Tetrapeptide
ASJC Scopus subject areas
- Pharmacology
- Drug Discovery