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

Brinda Somanadhan, Santosh R. Kotturi, Chung Yan Leong, Robert P. Glover, Yicun Huang, Horst Flotow, Antony D. Buss, Martin J. Lear, Mark S. Butler

Research output: Contribution to journalArticle

7 Citations (Scopus)

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 IC 50 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-NH 2. 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.

Original languageEnglish
Pages (from-to)259-264
Number of pages6
JournalJournal of Antibiotics
Volume66
Issue number5
DOIs
Publication statusPublished - 2013 May 1

Keywords

  • Chitinophaga
  • Falcipain
  • Falcitidin
  • Malaria
  • Myxobacteria
  • Tetrapeptide

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery

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    Somanadhan, B., Kotturi, S. R., Yan Leong, C., Glover, R. P., Huang, Y., Flotow, H., Buss, A. D., Lear, M. J., & Butler, M. S. (2013). Isolation and synthesis of falcitidin, a novel myxobacterial-derived acyltetrapeptide with activity against the malaria target falcipain-2. Journal of Antibiotics, 66(5), 259-264. https://doi.org/10.1038/ja.2012.123