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: Brinda Somanadhan, Santosh R Kotturi, Chung Yan Leong, Robert P Glover, Yicun Huang, Horst Flotow, Antony D Buss, Martin J Lear, Mark S Butler
• Journal: The Journal of antibiotics (J Antibiot (Tokyo)) Vol. 66 Issue 5 Pg. 259-64 (May 2013) ISSN: 1881-1469 [Electronic] England
• PMID: 23340660 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antimalarials
• Oligopeptides
• Protease Inhibitors
• Cysteine Endopeptidases
• falcipain 2

Topics

• Antimalarials (chemical synthesis, chemistry, isolation & purification, pharmacology)
• Bacteroidetes (chemistry, isolation & purification)
• Biological Assay
• Cysteine Endopeptidases (metabolism)
• Drug Evaluation, Preclinical
• Humans
• Inhibitory Concentration 50
• Magnetic Resonance Spectroscopy
• Molecular Structure
• Oligopeptides (chemical synthesis, chemistry, isolation & purification, pharmacology)
• Protease Inhibitors (chemical synthesis, chemistry, isolation & purification, pharmacology)
• Singapore
• Soil Microbiology
• Tandem Mass Spectrometry