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https://hdl.handle.net/2440/123264
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Type: | Journal article |
Title: | Reverse biosynthesis: generating combinatorial pools of drug leads from enzyme-mediated fragmentation of natural products |
Author: | Richardson-Sanchez, T. Tieu, W. Codd, R. |
Citation: | ChemBioChem: a European journal of chemical biology, 2017; 18(4):368-373 |
Publisher: | Wiley |
Issue Date: | 2017 |
ISSN: | 1439-4227 1439-7633 |
Statement of Responsibility: | Tomas Richardson-Sanchez, William Tieu, and Rachel Codd |
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: | Biological Products |
Description: | Final Article published: January 16, 2017 |
Rights: | © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim |
DOI: | 10.1002/cbic.201600636 |
Grant ID: | http://purl.org/au-research/grants/arc/DP140100092 |
Published version: | http://dx.doi.org/10.1002/cbic.201600636 |
Appears in Collections: | Aurora harvest 4 Molecular and Biomedical Science publications |
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