Elodie Marcon

Commissariat à l'Énergie Atomique et aux Énergies Alternatives

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Denis Servent

Technologies pour la Santé

Gilles Mourier

Commissariat à l'Énergie Atomique et aux Énergies Alternatives

Carole Fruchart‐Gaillard

CEA Paris-Saclay

David‐Alexandre Buisson

Commissariat à l'Énergie Atomique et aux Énergies Alternatives

Guillaume Blanchet

Commissariat à l'Énergie Atomique et aux Énergies Alternatives

Nicolas Gilles

Commissariat à l'Énergie Atomique et aux Énergies Alternatives

Sophie Feuillastre

Commissariat à l'Énergie Atomique et aux Énergies Alternatives

V. F. Pfeifer

Boehringer Ingelheim (Germany)

Bernard Gilquin

CEA Paris-Saclay

Grégory Pieters

Université Paris-Saclay

Cooperative Institutions

Commissariat à l'Énergie Atomique et aux Énergies Alternatives

CEA Paris-Saclay

Centre National de la Recherche Scientifique

Université Paris-Saclay

Institut de Biologie et Technologies

Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement

Université Paris Cité

Inserm

Technologies pour la Santé

Institut de Biologie Intégrative de la Cellule

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Pharmacological characterization of zinc and copper interaction with the human alpha1A-adrenoceptor

European Journal of Pharmacology (2011)

Justyna Ciolek Arhamatoulaye Maïga Elodie Marcon Denis Servent Nicolas Gilles

Affinities

10.1016/j.ejphar.2010.12.042

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Citations (18)

Structural Model of Ligand-G Protein-coupled Receptor (GPCR) Complex Based on Experimental Double Mutant Cycle Data

Journal of Biological Chemistry (2011)

Catherine Marquer Carole Fruchart‐Gaillard Guillaume Letellier Elodie Marcon Gilles Mourier

The snake toxin MT7 is a potent and specific allosteric modulator of the human M1 muscarinic receptor (hM1). We previously characterized by mutagenesis experiments the functional determinants of the MT7-hM1 receptor interaction (Fruchart-Gaillard, C., Mourier, G., Marquer, C., Stura, E., Birdsall, N. J., and Servent, D. (2008) Mol. Pharmacol. 74, 1554-1563) and more recently collected evidence indicating that MT7 may bind to a dimeric form of hM1 (Marquer, C., Fruchart-Gaillard, C., Mourier, G., Grandjean, O., Girard, E., le Maire, M., Brown, S., and Servent, D. (2010) Biol. Cell 102, 409-420). To structurally characterize the MT7-hM1 complex, we adopted a strategy combining double mutant cycle experiments and molecular modeling calculations. First, thirty-three ligand-receptor proximities were identified from the analysis of sixty-one double mutant binding affinities. Several toxin residues that are more than 25 Å apart still contact the same residues on the receptor. As a consequence, attempts to satisfy all the restraints by docking the toxin onto a single receptor failed. The toxin was then positioned onto two receptors during five independent flexible docking simulations. The different possible ligand and receptor extracellular loop conformations were described by performing simulations in explicit solvent. All the docking calculations converged to the same conformation of the MT7-hM1 dimer complex, satisfying the experimental restraints and in which (i) the toxin interacts with the extracellular side of the receptor, (ii) the tips of MT7 loops II and III contact one hM1 protomer, whereas the tip of loop I binds to the other protomer, and (iii) the hM1 dimeric interface involves the transmembrane helices TM6 and TM7. These results structurally support the high affinity and selectivity of the MT7-hM1 interaction and highlight the atypical mode of interaction of this allosteric ligand on its G protein-coupled receptor target.

Docking (animal)

10.1074/jbc.m111.261404

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Citations (39)

The Tumor Antigen Cyclin B1 Hosts Multiple CD4 T Cell Epitopes Differently Recognized by Pre-Existing Naive and Memory Cells in Both Healthy and Cancer Donors

The Journal of Immunology (2015)

Claire Chevaleyre Nadine Benhamouda Emmanuel Favry Elizabeth Fabre Anais Mhoumadi

Cyclin B1 (CCNB1) is considered as a potential target for a cancer vaccine, as it is overexpressed in many malignant cells, while being transiently expressed in normal cells. To evaluate the CD4 T cell response to CCNB1, we derived T cell lines by multiple weekly rounds of stimulation with recombinant CCNB1 of T cells collected in healthy donors (long-term T cell assays). T cell lines were specific for 15 immunodominant peptides and derived preferentially from naive T cells. From 74 overlapping peptides, 20 peptides were selected for their broad specificity of binding to HLA class II molecules and included most of the immunodominant epitopes. They primed in vitro a large number of specific CD4 T cell lines in all the donors. Immunodominant epitopes were the most efficacious in long-term T cell assays, both in terms of number of specific T cell lines and number of responding donors. The 20 peptides were also submitted to short-term T cell assays using cells collected in healthy and cancer patients with the aim to evaluate the memory response. The recognized peptides differed from the immunodominant peptides and were part of the best promiscuous peptides. We also observed pre-existing CCNB1-specifc IgG Abs in both healthy and cancer donors. Long- and short-term T cell assays revealed that CCNB1 contained many CD4 T cell epitopes, which are differentially recognized by pre-existing naive and memory CD4 T cells. These observations are of value for the design of cancer vaccines.

10.4049/jimmunol.1402548

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Citations (17)

Polypharmacology profiles and phylogenetic analysis of three-finger toxins from mamba venom: Case of aminergic toxins

Biochimie (2014)

Guillaume Blanchet Guillaume Collet Gilles Mourier Nicolas Gilles Carole Fruchart‐Gaillard

10.1016/j.biochi.2014.04.009

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Citations (25)

CD4 T cells specific for factor VIII are present at high frequency in healthy donors and comprise naïve and memory cells

Blood Advances (2017)

Sylvain Meunier Catherine Menier Elodie Marcon Sébastien Lacroix‐Desmazes Bernard Maillère

Key Points Many CD4 T cells specific for FVIII escape thymic selection in healthy donors, revealing a low central tolerance to FVIII. Some FVIII-specific CD4 T cells are differentiated into memory cells but do not expand.

10.1182/bloodadvances.2017008706

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Citations (27)

Molecular exploration of the α_1A‐adrenoceptor orthosteric site: Binding site definition for epinephrine, HEAT and prazosin

FEBS Letters (2014)

Arhamatoulaye Maïga Mélanie Dupont Guillaume Blanchet Elodie Marcon Bernard Gilquin

Despite the physiological and pharmacological importance of the α 1A ‐adrenoreceptor, the mode of interactions of classical agonists and radioactive ligands with this receptor is not yet clearly defined. Here, we used mutagenesis studies and binding experiments to evaluate the importance of 11 receptor sites for the binding of 125 I‐HEAT, 3 H‐prazosin and epinephrine. Only one residue (F312) commonly interacts with the three molecules, and, surprisingly, D106 interacts only with epinephrine in a moderate way. Our docking model shows that prazosin and HEAT are almost superimposed into the orthosteric pocket with their tetralone and quinazoline rings close to the phenyl ring of the agonist.

Docking (animal)

10.1016/j.febslet.2014.10.033

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Citations (12)

High Therapeutic Efficacy of a New Survivin LSP-Cancer Vaccine Containing CD4+ and CD8+ T-Cell Epitopes

Frontiers in Oncology (2018)

Fanny Onodi Chahrazed Maherzi-Mechalikh Alice Mougel Nadine Benhamouda Charlotte Taboas

The efficacy of an antitumoral vaccine relies both on the choice of the antigen targeted and on its design. The tumor antigen survivin is an attractive target to develop therapeutic cancer vaccines because of its restricted over-expression and vital functions in most human tumors. Accordingly, several clinical trials targeting survivin in various cancer indications have been conducted. Most of them relied on short peptide-based vaccines and showed promising, but limited clinical results. In this study, we investigated the immunogenicity and therapeutic efficacy of a new long synthetic peptide (LSP)-based cancer vaccine targeting the tumor antigen survivin (SVX). This SVX vaccine is composed of three long synthetic peptides containing several CD4+ and CD8+ T-cell epitopes, which bind to various HLA class II and class I molecules. Studies in healthy individuals showed CD4+ and CD8+ T-cell immunogenicity of SVX peptides in human, irrespective of the individual's HLA types. Importantly, high frequencies of spontaneous T-cell precursors specific to SVX peptides were also detected in the blood of various cancer patients, demonstrating the absence of tolerance against these peptides. We then demonstrated SVX vaccine's high therapeutic efficacy against four different established murine tumor models, associated with its capacity to generate both specific cytotoxic CD8+ and multifunctional Th1 CD4+ T-cell responses. When tumors were eradicated, generated memory T-cell responses protected against rechallenge allowing long-term protection against relapses. Treatment with SVX vaccine was also found to reshape the tumor microenvironment by increasing the tumor infiltration of both CD4+ and CD8+ T cells but not Treg cells therefore tipping the balance toward a highly efficient immune response. These results highlight that this LSP-based SVX vaccine appears as a promising cancer vaccine and warrants its further clinical development.

Survivin

Peptide vaccine

Cancer vaccine

Tumor Antigen

10.3389/fonc.2018.00517

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Citations (23)

DYNAMIC CARBON ISOTOPE EXCHANGE OF PHARMACEUTICALS WITH LABELED CO 2

Proceedings of European Symposium on Organic Chemistry 2019 (2019)

Gianluca Destro Olivier Loreau Elodie Marcon Frédéric Taran Thibault Cantat

Carbon fibers

Carbon-14

Source

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Citations (20)

140. Identification, Pharmacological and Structural characterization and Engineering of Three-finger Toxins interacting with GPCRs

Toxicon (2012)

Guillaume Blanchet Gilles Mourier Elodie Marcon Bernard Gilquin Nicolas Gilles

Identification

Characterization

10.1016/j.toxicon.2012.04.141

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Citations (0)

Engineering of Three-Finger Fold Toxins Creates Ligands with Original Pharmacological Profiles for Muscarinic and Adrenergic Receptors

PLoS ONE (2012)

Carole Fruchart‐Gaillard Gilles Mourier Guillaume Blanchet Laura Vera Nicolas Gilles

Protein engineering approaches are often a combination of rational design and directed evolution using display technologies. Here, we test "loop grafting," a rational design method, on three-finger fold proteins. These small reticulated proteins have exceptional affinity and specificity for their diverse molecular targets, display protease-resistance, and are highly stable and poorly immunogenic. The wealth of structural knowledge makes them good candidates for protein engineering of new functionality. Our goal is to enhance the efficacy of these mini-proteins by modifying their pharmacological properties in order to extend their use in imaging, diagnostics and therapeutic applications. Using the interaction of three-finger fold toxins with muscarinic and adrenergic receptors as a model, chimeric toxins have been engineered by substituting loops on toxin MT7 by those from toxin MT1. The pharmacological impact of these grafts was examined using binding experiments on muscarinic receptors M1 and M4 and on the α(1A)-adrenoceptor. Some of the designed chimeric proteins have impressive gain of function on certain receptor subtypes achieving an original selectivity profile with high affinity for muscarinic receptor M1 and α(1A)-adrenoceptor. Structure-function analysis supported by crystallographic data for MT1 and two chimeras permits a molecular based interpretation of these gains and details the merits of this protein engineering technique. The results obtained shed light on how loop permutation can be used to design new three-finger proteins with original pharmacological profiles.

Protein Engineering

Rational design

Chimera (genetics)

10.1371/journal.pone.0039166

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Citations (28)