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Issue 22, 2015
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Base-modified NAD and AMP derivatives and their activity against bacterial DNA ligases

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Abstract

We report the chemical synthesis and conformational analysis of a collection of 2-, 6- and 8-substituted derivatives of β-NAD+ and AMP, and their biochemical evaluation against NAD+-dependent DNA ligases from Escherichia coli and Mycobacterium tuberculosis. Bacterial DNA ligases are validated anti-microbial targets, and new strategies for their inhibition are therefore of considerable scientific and practical interest. Our study includes several pairs of β-NAD+ and AMP derivatives with the same substitution pattern at the adenine base. This has enabled the first direct comparison of co-substrate and inhibitor behaviour against bacterial DNA ligases. Our results suggest that an additional substituent in position 6 or 8 of the adenine base in β-NAD+ is detrimental for activity as either co-substrate or inhibitor. In contrast, substituents in position 2 are not only tolerated, but appear to give rise to a new mode of inhibition, which targets the conformational changes these DNA ligases undergo during catalysis. Using a molecular modelling approach, we highlight that these findings have important implications for our understanding of ligase mechanism and inhibition, and may provide a promising starting point for the rational design of a new class of inhibitors against NAD+-dependent DNA ligases.

Graphical abstract: Base-modified NAD and AMP derivatives and their activity against bacterial DNA ligases

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Publication details

The article was received on 10 Feb 2015, accepted on 07 May 2015 and first published on 14 May 2015


Article type: Paper
DOI: 10.1039/C5OB00294J
Author version available: Download Author version (PDF)
Citation: Org. Biomol. Chem., 2015,13, 6380-6398
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    Base-modified NAD and AMP derivatives and their activity against bacterial DNA ligases

    G. Pergolizzi, M. M. D. Cominetti, J. N. Butt, R. A. Field, R. P. Bowater and G. K. Wagner, Org. Biomol. Chem., 2015, 13, 6380
    DOI: 10.1039/C5OB00294J

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