We are currently developing modified nucleos(t)ides as substrate mimics to provide insight into enzyme substrate recognition, as well as libraries of functionalized heterocycles useful for the fragment based approach. Novel enzymatic routes (transglycosylation, deamination, phosphorylation) as an alternative to chemical approaches are also considered. The synthesized molecules find applications in the identification of inhibitors of essential bacterial enzymes (TMPK from Mycobacterium tuberculosis, DNPH1, an N-hydrolase involved in cell proliferation, NAD kinases from Gram-positive bacteria). In addition, the new chemical entities implement the in house chemical libraries.
Inhibitors of bacterial NAD kinases
NAD mimics as potential antibacterial agents The NAD(P) biosynthesis pathways have attracted recent interest as a source of enzyme targets for the development of antimicrobial agents. Our own research focused on the structure-based development […]
Protein synthesis machinery of Trypanosomatid as a therapeutic target
Pathogenic protozoans of the trypanosomatid group still remain a major world health problem. Cycling between insect vectors and mammalian hosts, Trypanosoma cruzi is the causative agent of Chagas disease, while over 20 Leishmania species […]
Inhibitors of the 2’-deoxyribonucleotide N-hydrolase DNPH1, an enzyme involved in cellular growth and angiogenesis
Nucleoside analogues as potential antitumor agents. This project aims to characterize and validate the nucleotide N-hydrolase DNPH1 as a new target in oncology. Inhibition of Rcl alone or in combination with other chemotherapeutic drugs […]
Inhibitors of Pseudomonas aeruginosa IMPDH
IMPDH from Pseudomonas aeruginosa (see Inosine-5′-monophosphate dehydrogenase project) was found to be allosterically regulated by MgATP (Labesse et al., 2013). The discovery of this mode of regulation of the catalytic activity, never described before […]
Inhibitors of TMPK from Mycobacterium tuberculosis
TMPK from Mycobacterium tuberculosis belongs to the NMPK family, which was chosen as potential targets for the development of new antimicrobials (see “Nucleoside monophosphate kinases” project). Based on the 3D-structure of TMPK from M. […]
2021Noncanonical DNA polymerization by aminoadenine-based siphoviruses., Science 2021 04; 372(6541): 520-524.
2020New Chemical Probe Targeting Bacterial NAD Kinase., Molecules 2020 Oct; 25(21): .
2020Fermentation Products of Commensal Bacteria Alter Enterocyte Lipid Metabolism, Cell Host Microbe 2020 March 11;27:1-18.
2020From Substrate to Fragments to Inhibitor Active In Vivo against Staphylococcus aureus., ACS Infect Dis 2020 03; 6(3): 422-435.
2020An expedient synthesis of flexible nucleosides through enzymatic glycosylation of proximal and distal fleximer bases, Chembiochem 2020 Jan;.
2019Crystal structure of the Trypanosoma cruzi EIF4E5 translation factor homologue in complex with mRNA cap-4, Nucleic Acids Res. 2019 Jun;47(11):5973-5987.
2019First-in-class allosteric inhibitors of bacterial IMPDHs, Eur J Med Chem 2019 Feb;167:124-132.
20192′-Deoxyribonucleoside 5′-triphosphates bearing 4-phenyl and 4-pyrimidinyl imidazoles as DNA polymerase substrates, Org. Biomol. Chem. 2019 01;17(2):290-301.
2018Enzymatic synthesis of random sequences of RNA and RNA analogues by DNA polymerase theta mutants for the generation of aptamer libraries, Nucleic Acids Res. 2018 07;46(12):6271-6284.
2017An expedient synthesis of flexible nucleosides via a regiocontrolled enzymatic glycosylation of functionalized imidazoles, Org. Biomol. Chem., 2017, 15, 8193.
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