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

Somanadhan, Brinda, Kotturi, Santosh R., Yan Leong, Chung , Glover, Robert P., Huang, Yicun, Flotow, Horst, Buss, Antony D., 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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