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Chembiochem. 2017 Feb 16;18(4):368-373. doi: 10.1002/cbic.201600636. Epub 2017 Jan 16.

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

Author information

1
School of Medical Sciences (Pharmacology), The University of Sydney, Camperdown, NSW, 2006, Australia.

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.

KEYWORDS:

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

PMID:
27943581
DOI:
10.1002/cbic.201600636
[Indexed for MEDLINE]

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