High throughput discovery of heteroaromatic-modifying enzymes allows enhancement of novobiocin selectivity

Sital M. Patel; Maria de la Fuente; Song Ke; Andreia M. R. Guimarães; Adeola O. Oliyide; Xiaoyun Ji; Paul Stapleton; Anne Osbourn; Yi Pan; Dianna J. Bowles; Benjamin G. Davis; Andreas Schatzlein; Min Yang

doi:10.1039/C1CC13552J

High throughput discovery of heteroaromatic-modifying enzymes allows enhancement of novobiocin selectivity†

Sital M. Patel,^a Maria de la Fuente,^a Song Ke,^a Andreia M. R. Guimarães,^a Adeola O. Oliyide,^a Xiaoyun Ji,^b Paul Stapleton,^a Anne Osbourn,^c Yi Pan,^b Dianna J. Bowles,^d Benjamin G. Davis,^e Andreas Schatzlein^a and Min Yang*^a

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^a Department of Pharmaceutical & Biological Chemistry, The School of Pharmacy, University of London, 29/39 Brunswick Square, London, UK
E-mail: min.yang@pharmacy.ac.uk
Fax: + 44(0)2077535964
Tel: + 44(0)2077535876

^b School of Chemistry and Chemical Engineering, Nanjing University, No. 22 Hankou Road, Gulou District, Nanjing, China

^c Department of Metabolic Biology, John Innes Centre, Colney Lane, Norwich NR4 7UH, UK

^d Department of Biology, University of York, York, UK

^e Department of Chemistry, University of Oxford, CRL, Mansfield Road, Oxford, UK

Abstract

Glycosylated analogues of novobiocin, discovered using a broad library of enzymes, have 100-fold improved activity against breast, brain, pancreatic, lung and ovarian cancers and ablated associated off-target activity leading to an up to 2.7 × 10⁴ fold increase in selectivity.

Chemical Communications

High throughput discovery of heteroaromatic-modifying enzymes allows enhancement of novobiocin selectivity†

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High throughput discovery of heteroaromatic-modifying enzymes allows enhancement of novobiocin selectivity

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