Reverse Biosynthesis: Generating Combinatorial Pools of Drug Leads from Enzyme-Mediated Fragmentation of Natural Products

Tomas Richardson-Sanchez, William Tieu, Rachel Codd

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)

Abstract

A combinatorial pool of hydroxamic acid fragments as potential metalloprotein drug leads was generated from the enzymatic hydrolysis of the natural product desferrioxamine B (DFOB). DFOB is a metabolite produced by Streptomyces pilosus for iron acquisition, and can be selectively catabolised by Niveispirillum irakense to access carbon for growth. The supernatant of a DFOB-supplemented culture of N. irakense was analysed by LC-MS at intervals over 168 h. This identified a mixture of endo-hydroxamic acid fragments that contained reactive terminal groups. The supernatants from two cultures (at 48 h and 168 h) were reacted with 1,8-naphthalic anhydride in a microwave synthesiser to generate pools of scriptaid analogues, which were screened against ZnII-containing histone deacetylases (HDACs) and FeIII-containing 5-lipoxygenase (5-LO). Compound S2 showed relative potency against 5-LO (IC50=59 μm; BWA4C, 17 μm); it was 28-fold more selective towards 5-LO than HDAC1. Compound S1 inhibited HDAC1 but not 5-LO. Enzyme-mediated reverse biosynthesis could yield new benefits from structurally complex natural products in drug design.

Original languageEnglish
Pages (from-to)368-373
Number of pages6
JournalChemBioChem
Volume18
Issue number4
DOIs
Publication statusPublished or Issued - 16 Feb 2017

Keywords

  • bacterial interspecies interactions
  • combinatorial drug discovery
  • inhibitors
  • natural products
  • reverse biosynthesis

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Organic Chemistry

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