PEYROTTES Suzanne
Team: Nucléosides & Effecteurs Phosphorylés
suzanne.peyrottes
umontpellier.fr
0448792053
Room: 0N1H12 - Site : Pôle Chimie Balard Recherche
Research Topics: - chim/chim.chem
- chim/chim.orga
- sdv/sdv.bbm/sdv.bbm.bs
- sdv/sdv.can
- chim/chim.anal
- chim/chim.ther
- sdv/sdv.bbm/sdv.bbm.bc
- sdv/sdv.bc
- sdv/sdv.bibs
- info/info.info-bi
- sdv/sdv.mhep/sdv.mhep.derm
- sdv/sdv.imm/sdv.imm.ii
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Last scientific productions :
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Identification of allosteric inhibitors of the ecto-5'-nucleotidase (CD73) targeting the dimer interface
Author(s): Rahimova Rahila, Fontanel Simon, Lionne Corinne, Jordheim Lars Peter, Peyrottes S., Chaloin Laurent
(Article) Published:
Plos Computational Biology, vol. 14 p. (2018)
Ref HAL: hal-01838257_v1
DOI: 10.1371/journal.pcbi.1005943
Abstract: The ecto-5’-nucleotidase CD73 plays an important role in the production of immune-suppressive adenosine in tumor micro-environment, and has become a validated drug target in oncology. Indeed, the anticancer immune response involves extracellular ATP to block cell proliferation through T-cell activation. However, in the tumor micro-environment, two extracellular membrane-bound enzymes (CD39 and CD73) are overexpressed and hydrolyze efficiently ATP into AMP then further into immune-suppressive adenosine. To circumvent the impact of CD73-generated adenosine, we applied an original bioinformatics approach to identify new allosteric inhibitors targeting the dimerization interface of CD73, which should impair the large dynamic motions required for its enzymatic function. Several hit compounds issued from virtual screening campaigns showed a potent inhibition of recombinant CD73 with inhibition constants in the low micromolar range and exhibited a non-competitive inhibition mode. The structure-activity relationships studies indicated that several amino acid residues (D366, H456, K471, Y484 and E543 for polar interactions and G453-454, I455, H456, L475, V542 and G544 for hydrophobic contacts) located at the dimerization interface are involved in the tight binding of hit compounds and likely contributed for their inhibitory activity. Overall, the gathered information will guide the upcoming lead optimization phase that may lead to potent and selective CD73 inhibitors, able to restore the anticancer immune response.
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Determination and quantification of intracellular fludarabine triphosphate, cladribine triphosphate and clofarabine triphosphate by LC-MS/MS in human cancer cells.
Author(s): Puy J.-Y., Jordheim Lars Petter, Cros-Perrial Emeline, Dumontet Charles, Peyrottes S., Lefebvre-Tournier I.
(Article) Published:
-Journal Of Chromatography B Analytical Technologies In The Biomedical And Life Sciences, vol. 1053 p.101-110 (2017)
Ref HAL: hal-01567793_v1
PMID 28415014
Abstract: Purine nucleoside analogues are widely used in the treatment of haematological malignancies, and their biological activity is dependent on the intracellular accumulation of their triphosphorylated metabolites. In this context, we developed and validated a liquid chromatography tandem mass spectrometry (LC-MS/MS) method to study the formation of 5'-triphosphorylated derivatives of cladribine, fludarabine, clofarabine and 2'-deoxyadenosine in human cancer cells. Br-ATP was used as internal standard. Separation was achieved on a hypercarb column. Analytes were eluted with a mixture of hexylamine (5 mM), DEA (0.4%, v/v, pH 10.5) and acetonitrile, in a gradient mode at a flow rate of 0.3mLmin(-1). Multiple reactions monitoring (MRM) and electrospray ionization in negative mode (ESI-) were used for detection. The application of this method to the quantification of these phosphorylated cytotoxic compounds in a human follicular lymphoma cell line, showed that it was suitable for the study of relevant biological samples.
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Beta-hydroxyphosphonate ribonucleoside analogues derived from 4-substituted-1,2,3-triazoles as IMP/GMP mimics: synthesis and biological evaluation
Author(s): Nguyen V. T., Hospital A., Lionne C., Jordheim L.P., Dumontet C., Perigaud C., Chaloin L., Peyrottes S.
(Article) Published:
Beilstein Journal Of Organic Chemistry, vol. 12 p.1476--1486 (2016)
Ref HAL: hal-01812668_v1
PMID 27559400
DOI: 10.3762/bjoc.12.144
Abstract: A series of seventeen beta-hydroxyphosphonate ribonucleoside analogues containing 4-substituted-1,2,3-triazoles was synthesized and fully characterized. Such compounds were designed as potential inhibitors of the cytosolic 5'-nucleotidase II (cN-II), an enzyme involved in the regulation of purine nucleotide pools. NMR and molecular modelling studies showed that a few derivatives adopted similar structural features to IMP or GMP. Five derivatives were identified as modest inhibitors with 53 to 64% of cN-II inhibition at 1 mM
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Identification of noncompetitive inhibitors of cytosolic 5′-nucleotidase II using a fragment-based approach
Author(s): Marton Zsuzsanna, Guillon R., Krimm Isabelle, Rahimova Rahila, Egron D., Jordheim Lars P., Aghajari Nushin, Dumontet Charles, Perigaud C., Lionne Corinne, Peyrottes S., Chaloin Laurent
(Article) Published:
European Journal Of Medicinal Chemistry, vol. 58 p.9680-9696 (2015)
Ref HAL: hal-01251800_v1
PMID 26599519
DOI: 10.1021/acs.jmedchem.5b01616
Abstract: We used a combined approach based on fragment-based drug design (FBDD) and in silico methods to design potential inhibitors of the cytosolic 5'-nucleotidase II (cN-II), which has been recognized as an important therapeutic target in hematological cancers. Two subgroups of small compounds (including adenine and biaryl moieties) were identified as cN-II binders and a fragment growing strategy guided by molecular docking was considered. Five compounds induced a strong inhibition of the 5'-nucleotidase activity in vitro, and the most potent ones were characterized as noncompetitive inhibitors. Biological evaluation in cancer cell lines showed synergic effect with selected anticancer drugs. Structural studies using X-ray crystallography lead to the identification of new binding sites for two derivatives and of a new crystal form showing important domain swapping. Altogether, the strategy developed herein allowed identifying new original noncompetitive inhibitors against cN-II that act in a synergistic manner with well-known antitumoral agents.
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A Chemical Proteomics Approach for the Search of Pharmacological Targets of the Antimalarial Clinical Candidate Albitiazolium in Plasmodium falciparum Using Photocrosslinking and Click Chemistry.
Author(s): Penarete-Vargas Diana Marcela, Boisson Anaïs, Urbach Serge, Chantelauze H., Peyrottes S., Fraisse Laurent, Vial Henri J
(Article) Published:
Plos One, vol. 9 p.1-23 (2014)
Ref HAL: hal-01101633_v1
DOI: 10.1371/journal.pone.0113918
Abstract: Plasmodium falciparum is responsible for severe malaria which is one of the most prevalent and deadly infectious diseases in the world. The antimalarial therapeutic arsenal is hampered by the onset of resistance to all known pharmacological classes of compounds, so new drugs with novel mechanisms of action are critically needed. Albitiazolium is a clinical antimalarial candidate from a series of choline analogs designed to inhibit plasmodial phospholipid metabolism. Here we developed an original chemical proteomic approach to identify parasite proteins targeted by albitiazolium during their native interaction in living parasites. We designed a bifunctional albitiazolium-derived compound (photoactivable and clickable) to covalently crosslink drug–interacting parasite proteins in situ followed by their isolation via click chemistry reactions. Mass spectrometry analysis of drug–interacting proteins and subsequent clustering on gene ontology terms revealed parasite proteins involved in lipid metabolic activities and, interestingly, also in lipid binding, transport, and vesicular transport functions. In accordance with this, the albitiazolium-derivative was localized in the endoplasmic reticulum and trans-Golgi network of P. falciparum. Importantly, during competitive assays with albitiazolium, the binding of choline/ethanolamine phosphotransferase (the enzyme involved in the last step of phosphatidylcholine synthesis) was substantially displaced, thus confirming the efficiency of this strategy for searching albitiazolium targets.
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