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  3. Synthesis and structure-activity relationship studies of original cyclic diadenosine derivatives as nanomolar inhibitors of NAD kinase from pathogenic bacteria

Synthesis and structure-activity relationship studies of original cyclic diadenosine derivatives as nanomolar inhibitors of NAD kinase from pathogenic bacteria

  • Eur J Med Chem. 2022 Nov 23;246:114941. doi: 10.1016/j.ejmech.2022.114941.
David A Clément 1,  Muriel Gelin 2,  Clarisse Leseigneur 3,  Valérie Huteau 1,  Lou Mondange 3,  Jean-Luc Pons 2,  Olivier Dussurget 3,  Corinne Lionne 2,  Gilles Labesse 4,  Sylvie Pochet 5
Affiliations

Affiliations

  • 1 Institut Pasteur, Université Paris Cité, CNRS UMR3523, Unité de Chimie et Biocatalyse, F-75015, Paris, France.
  • 2 Centre de Biologie Structurale (CBS), CNRS UMR5048, INSERM U1054, Université de Montpellier, 34090, Montpellier, France.
  • 3 Institut Pasteur, Université Paris Cité, CNRS UMR6047, Unité de Recherche Yersinia, F-75015, Paris, France.
  • 4 Centre de Biologie Structurale (CBS), CNRS UMR5048, INSERM U1054, Université de Montpellier, 34090, Montpellier, France. Electronic address: gilles.labesse@cbs.cnrs.fr.
  • 5 Institut Pasteur, Université Paris Cité, CNRS UMR3523, Unité de Chimie et Biocatalyse, F-75015, Paris, France. Electronic address: sylvie.pochet@pasteur.fr.
PMID: 36455355 DOI: 10.1016/j.ejmech.2022.114941
Abstract

Nicotinamide adenine dinucleotide kinases (NAD kinases) are essential and ubiquitous Enzymes involved in the production of NADP(H) which is an essential cofactor in many metabolic pathways. Targeting NAD kinase (NADK), a rate limiting Enzyme of NADP biosynthesis pathway, represents a new promising approach to treat Bacterial infections. Previously, we have produced the first NADK inhibitor active against staphylococcal Infection. From this linear di-adenosine derivative, namely NKI1, we designed macrocyclic analogues. Here, we describe the synthesis and evaluation of an original series of cyclic diadenosine derivatives as NADK inhibitors of two pathogenic bacteria, Listeria monocytogenes and Staphylococcus aureus. The nature and length of the link between the two adenosine units were examined leading to sub-micromolar inhibitors of NADK1 from L. monocytogenes, including its most potent in vitro inhibitor reported so far (with a 300-fold improvement compared to NKI1).

Keywords

Crystal structure; Inhibitor; Listeria; Macrocyclic compound; NAD kinase; Staphylococcus.

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