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Base-modified NAD and AMP derivatives and their activity against bacterial DNA ligases.

Authors
  • Pergolizzi, Giulia
  • Cominetti, Marco M D
  • Butt, Julea N
  • Field, Robert A
  • Bowater, Richard P
  • Wagner, Gerd K
Type
Published Article
Journal
Organic & Biomolecular Chemistry
Publisher
The Royal Society of Chemistry
Publication Date
Jun 14, 2015
Volume
13
Issue
22
Pages
6380–6398
Identifiers
DOI: 10.1039/c5ob00294j
PMID: 25974621
Source
Medline
License
Unknown

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.

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