title: Isolation and synthesis of falcitidin, a novel myxobacterial-derived acyltetrapeptide with activity against the malaria target falcipain-2.
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.
authors: MerLion Pharmaceuticals, Singapore, Singapore.
authors: Brinda
authors: B
authors: Somanadhan
authors: Santosh R
authors: SR
authors: Kotturi
authors: Chung
authors: C
authors: Yan Leong
authors: Robert P
authors: RP
authors: Glover
authors: Yicun
authors: Y
authors: Huang
authors: Horst
authors: H
authors: Flotow
authors: Antony D
authors: AD
authors: Buss
authors: Martin J
authors: MJ
authors: Lear
authors: Mark S
authors: MS
authors: Butler
mesh_terms: D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D041963:Bacteroidetes / Q000737:chemistry / Q000302:isolation & purification; D001681:Biological Assay; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical; D006801:Humans; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D012846:Singapore; D012988:Soil Microbiology; D053719:Tandem Mass Spectrometry
chemical_list: D000962:Antimalarials; D009842:Oligopeptides; D011480:Protease Inhibitors; D003546:Cysteine Endopeptidases; C416224:falcipain 2