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 IC50 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-NH2. 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.
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Acknowledgements
We thank the National University of Singapore for a Graduate Scholarship (to SRK) and generous funding from the National Medical Research Council (NMRC/IRG11may097) of Singapore (to MJL).
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Somanadhan, B., Kotturi, S., Yan Leong, C. et al. Isolation and synthesis of falcitidin, a novel myxobacterial-derived acyltetrapeptide with activity against the malaria target falcipain-2. J Antibiot 66, 259–264 (2013). https://doi.org/10.1038/ja.2012.123
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DOI: https://doi.org/10.1038/ja.2012.123
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