Isolation and synthesis of falcitidin, a novel myxobacterial-derived acyltetrapeptide with activity against the malaria target falcipain-2

Somanadhan, Brinda and Kotturi, Santosh R. and Yan Leong, Chung and Glover, Robert P. and Huang, Yicun and Flotow, Horst and Buss, Antony D. and Lear, Martin J. and Butler, Mark S. (2013) Isolation and synthesis of falcitidin, a novel myxobacterial-derived acyltetrapeptide with activity against the malaria target falcipain-2. The Journal of Antibiotics, 66 (5). pp. 259-264. ISSN 0021-8820

Full content URL: http://dx.doi.org/10.1038/ja.2012.123

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Isolation and synthesis of falcitidin, a novel myxobacterial-derived acyltetrapeptide with activity against the malaria target falcipain-2

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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 mycobacterium 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 mM 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 (o100 mg 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.

Keywords:Chitinophaga, falcipain, falcitidin, malaria, myxobacteria, tetrapeptide
Subjects:F Physical Sciences > F160 Organic Chemistry
F Physical Sciences > F150 Medicinal Chemistry
Divisions:College of Science > School of Chemistry
ID Code:17102
Deposited On:17 Apr 2015 09:06

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