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

Article

Author: Labesse, Gilles ; Pons, Jean-Luc ; Clément, David A ; Gelin, Muriel ; Leseigneur, Clarisse ; Lionne, Corinne ; Dussurget, Olivier ; Huteau, Valérie ; Mondange, Lou ; Pochet, Sylvie

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).

MoleculesQ3 · CHEMISTRY

New Chemical Probe Targeting Bacterial NAD Kinase

Q3 · CHEMISTRY

ArticleOA

Author: Leseigneur, Clarisse ; Labesse, Gilles ; Coelho, Dylan ; Dussurget, Olivier ; Clément, David A ; Gelin, Muriel ; Pochet, Sylvie ; Huteau, Valérie ; Lionne, Corinne

Nicotinamide adenine dinucleotide (NAD) kinases are essential and ubiquitous enzymes involved in the tight regulation of NAD/nicotinamide adenine dinucleotide phosphate (NADP) levels in many metabolic pathways. Consequently, they represent promising therapeutic targets in cancer and antibacterial treatments. We previously reported diadenosine derivatives as NAD kinase inhibitors with bactericidal activities on Staphylococcus aureus. Among them, one compound (namely NKI1) was found effective in vivo in a mouse infection model. With the aim to gain detailed knowledge about the selectivity and mechanism of action of this lead compound, we planned to develop a chemical probe that could be used in affinity-based chemoproteomic approaches. Here, we describe the first functionalized chemical probe targeting a bacterial NAD kinase. Aminoalkyl functional groups were introduced on NKI1 for further covalent coupling to an activated SepharoseTM matrix. Inhibitory properties of functionalized NKI1 derivatives together with X-ray characterization of their complexes with the NAD kinase led to identify candidate compounds that are amenable to covalent coupling to a matrix.

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Indication	Highest Phase	Country/Location	Organization	Date
Staphylococcal Infections	Preclinical	FR	Universite de Montpellier II	-
Staphylococcal Infections	Preclinical	FR	Institut Pasteur	-
Staphylococcal Infections	Preclinical	FR	Institut Curie	-

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