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

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, l...

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Veröffentlicht in:	Journal of antibiotics 2013-05, Vol.66 (5), p.259-264
Hauptverfasser:	Somanadhan, Brinda, Kotturi, Santosh R, Yan Leong, Chung, Glover, Robert P, Huang, Yicun, Flotow, Horst, Buss, Antony D, Lear, Martin J, Butler, Mark S
Format:	Artikel
Sprache:	eng
Schlagworte:	631/326/22/1290 631/535 692/699/255/1629 Antimalarials - chemical synthesis Antimalarials - chemistry Antimalarials - isolation & purification Antimalarials - pharmacology Bacteriology Bacteroidetes - chemistry Bacteroidetes - isolation & purification Bioassays Biological Assay Biomedical and Life Sciences Bioorganic Chemistry Cysteine Endopeptidases - metabolism Drug Evaluation, Preclinical Humans Inhibitors Inhibitory Concentration 50 Life Sciences Magnetic Resonance Spectroscopy Malaria Medicinal Chemistry Microbiology Molecular Structure Oligopeptides - chemical synthesis Oligopeptides - chemistry Oligopeptides - isolation & purification Oligopeptides - pharmacology Organic Chemistry original-article Protease Inhibitors - chemical synthesis Protease Inhibitors - chemistry Protease Inhibitors - isolation & purification Protease Inhibitors - pharmacology Singapore Soil Microbiology Tandem Mass Spectrometry Vector-borne diseases
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Zusammenfassung:	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 μ M 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 (
ISSN:	0021-8820 1881-1469
DOI:	10.1038/ja.2012.123