Isolation and synthesis of falcitidin, a novel myxobacterial-derived acyltetrapeptide with activity against the malaria target falcipain-2
Somanadhan, B. Kotturi, S.R. Yan Leong, C. Glover, R.P. Huang, Y. Flotow, H. Buss, A.D. Lear, M.J. Butler, M.S.
Somanadhan, B.
Yan Leong, C.
Glover, R.P.
Huang, Y.
Flotow, H.
Buss, A.D.
Butler, M.S.
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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. © 2013 Japan Antibiotics Research Association All rights reserved.
Keywords
Chitinophaga, Falcipain, Falcitidin, Malaria, Myxobacteria, Tetrapeptide
Source Title
Journal of Antibiotics
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Series/Report No.
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Date
2013-05
DOI
10.1038/ja.2012.123
Type
Article