title: Base-modified NAD and AMP derivatives and their activity against bacterial DNA ligases.
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.
authors.affiliation: School of Pharmacy, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, UK.
authors.forename: Giulia
authors.initials: G
authors.lastname: Pergolizzi
authors.forename: Marco M D
authors.initials: MM
authors.lastname: Cominetti
authors.forename: Julea N
authors.initials: JN
authors.lastname: Butt
authors.forename: Robert A
authors.initials: RA
authors.lastname: Field
authors.forename: Richard P
authors.initials: RP
authors.lastname: Bowater
authors.forename: Gerd K
authors.initials: GK
authors.lastname: Wagner
mesh_terms: D000249:Adenosine Monophosphate / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011088:DNA Ligases / Q000037:antagonists & inhibitors* / Q000302:isolation & purification / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology*; D008958:Models, Molecular; D008968:Molecular Conformation; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology*; D009243:NAD / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D009243:NAD; D000249:Adenosine Monophosphate; D011088:DNA Ligases