ERAP modulators

Team

  • Team Leader: Pr Rebecca Deprez-Poulain PhD - PharmD
  • Rodolphe Vatinel – PostDoc
  • Pierre Sierocki – PostDoc
  • Laetitia Lesire – PostDoc
  • Virgyl Camberlein – PhD student
  • Cyril Couturier – Ass Pr
  • Florence Leroux PhD - PharmD Biochemist
  • Adrien Herledan – Ass Eng
former members
  • Ronan Gealageas - PostDoc
  • Paul Hermant -PhD student
  • Keguang Cheng - PostDoc
  • Mission

    Discover chemical modulators of the ERAP 1 and/or 2 enzymes involved in antigen presentation

    Approach

    Many antigenic peptides presented by MHC class I molecules are initially created through proteolysis by the proteasome as precursors. The trimming of these precursors to the final epitope is performed in the ER by ERAP-1 and ERAP-2. Genome wide Association Studies have linked ERAP1 and ERAP2 with predisposition to human diseases with autoimmune aetiology such as rheumatic diseases (most notably Ankylosing Spondylitis), and type I diabetes as well as with bacterial and viral. Also, Pr Stratikos team in Athens has contributed significantly to the understanding of the function of these proteases and has published their 3D-structure. The available evidences for a significant impact of ERAP1/2 on human health suggest that pharmacological modulation of ERAP function may be of medical interest. So far, apart from non selective compounds such as amastin and leucinthiol, no selective and potent inhibitors of these enzymes are available.

    While the short term goal of this proposal will be the identification of promising leads, the long term goal will be the generation of novel pharmacological approaches towards the treatment of ERAP-associated human diseases based on the modulation of antigen processing and adaptive immune responses.

    Latest results

    The project “ERAPIMM” has been granted by ANR for 3 years (Nov 2020- Nov 2023).

    The teams of

    • Pr R. Deprez-Poulain (Coordinator, M2SV, INSERM U1177, Institut Pasteur de Lille, University of Lille),
    • Pr P. van Endert ( INEM, INSERM U1151 –CNRS UMR 8253, University of Paris)
    • Pr D. Launay (INFINITE, INSERM U1286, Lille Regional Hospital, University of Lille)

    collaborate in a project aiming at discovering and developing of  ERAP inhibitors as a new approach to treat autoimmune & auto-inflammatory diseases.

    In particular, the teams will specifically study applications in Type 1 diabetes, Behcet’s disease and Spondyloarthritis.

     

    The project CAPSTONE has been granted by EU MSCA for 4 years (Jan 2021-Dec 2024).

    Follow link to learn more about our Excellence Training Network

    National and international collaborations

    • Pr. van Endert, U1013 INSERM, Hopital Necker. Cell biology & antigenic presentation.
    • Dr. Stratikos, Demokritos Research Center, Athens, Greece. Cell Biology & X-ray.
    • CAPSTONE CONSORTIUM

    Grants

    • ANR Grant 2020-2023
    • H2020 MSCA ITN CAPSTONE 2021-2024
    • FRM Grant 2019-2021
    • IUF Grant 2015-2020
    • Campus France Hubert-Curien Grant 2013-2014

    Publications

    • Mpakali, A., Giastas, P., Deprez-Poulain, R., Papakyriakou, A., Koumantou, D., Gealageas, R., Tsoukalidou, S., Vourloumis, D., Mavridis, I. M., Stratikos, E., & Saridakis, E. Crystal Structures of ERAP2 Complexed with Inhibitors Reveal Pharmacophore Requirements for Optimizing Inhibitor Potency. ACS Medicinal Chemistry Letters, 2017, 8(3): 333-337.doi:10.1021/acsmedchemlett.6b00505

    Communications

    Conferences


    2019

    • Deprez-Poulain, R. Validating new metalloproteases targets in drug discovery using small molecules,GDCh-Wissenschaftsforum Chemie,GDCh,Aachen, Germany,15th-18th Sept. 2019 Invited.
    • Deprez-Poulain, R. Kinetic Target-Guided Synthesis as a Tool for Drug-Discovery: Successes, Challenges and Applications to Metalloproteases,2nd Molecules Medicinal Chemistry Symposium,Barcelona, Spain,15th-17th May 2019 Invited.

    2018

    • Deprez-Poulain, R. Pharmacological modulation of antigen processing and presentation: new therapeutic approach for cancer and autoimmune diseases,4th Scientific Meeting of the Institut Pasteur de Lille,Marcq en Baroeul, France,18 Jun. 2018 Invited

    • Deprez-Poulain, R. Nouveaux médicaments du cancer et des maladies auto-immunes : dompter le système immunitaire à des fins thérapeutiques,Conférences 5à7 Médicaments,Institut Pasteur de Lille, France,17th Apr. 2018

    Posters

    2019

    • Castillo-Aguilera, O., Rosell, M., Lam, B. V., Warenghem, S., Guillaume, V., Camberlein, V., Bosc, D., Leroux, F., Deprez, B., & Deprez-Poulain, R. Ullman-derived inhibitors of ER-aminopeptidases (ERAP) Drug Discovery Day, Lille, France, 18th jan,2019.
    • Castillo-Aguilera, O., Rosell, M., Lam, B. V., Warenghem, S., Guillaume, V., Camberlein, V., Bosc, D., Leroux, F., Deprez, B., & Deprez-Poulain, R. Ullman-derived inhibitors of ER-aminopeptidases (ERAP) 26th SCT Young Research Fellow Meeting, Paris, France, 20th-22nd Feb.,2019.

    2018

    • Lam, B. V., Gealageas, R., Warenghem, S., Guillaume, V., Camberleyn, V., Bosc, D., Leroux, F., Deprez, B., & Deprez-Poulain, R. Ullman-Derived Inhibitors Of Er-Aminopeptidases (Eraps). 54th International Conference on Medicinal Chemistry , Interfacing Chemical Biology and Drug Discovery, Strasbourg, France, 4th-6th July,2018.
    • Lam, B. V., Gealageas, R., Warenghem, S., Guillaume, V., Camberleyn, V., Bosc, D., Leroux, F., Deprez, B., & Deprez-Poulain, R. Ullman-Derived Inhibitors Of Er-Aminopeptidases (Eraps). XXV EFMC International Symposium on Medicinal Chemistry, Ljubljana, Slovenia 2nd-6th Sept.,2018.
    2017
     
    • Gealageas, R., Dassonneville, S., Dumont-Ryckembusch, J., Bosc, D., Lam, B.-V., Deprez, B., Florence, L., & Deprez-Poulain, R. Discovery of hERAP2 inhibitors by high-throughput screening in 384-format. Antigen processing and presentation, Salamanca, Spain, 28 – 31 May,2017.
    • Gealageas, R., Dassonneville, S., Dumont-Ryckembusch, J., Bosc, D., Lam, B. V., Deprez, B., Leroux, F., & Deprez-Poulain, R. Inhibitors of hERAP2 with unusual Zinc-binding group discovered by High-Throughput Screening in 384-well plate 53rd International Conference on Medicinal Chemistry (RICT), Toulouse, FR, 5th-7th July,2017.
    • Gealageas, R., Dassonneville, S., Dumont-Ryckembusch, J., Bosc, D., Lam, B. V., Hottin, A., Deprez, B., Leroux, F., & Deprez-Poulain, R. Inhibitors of hERAP2 with unusual Zinc-binding group discovered by High-throughput Screening in 384-well plate Drug Discovery Day, Master Seminar, School of Pharmacy, Lille, France, 7th Dec.,2017.

    2016

    • Hermant, P., Piveteau, C., Biela, A., Bosc, D., Roignant, M., Deprez, B., & Deprez-Poulain, R. Hit-to-Lead forecasting tools to prevent hydroxamic acids esterasic-metabolism in different species 52nd International Conference on Medicinal Chemistry, RICT 2016, Interfacing Chemical Biology and Drug Discovery, Caen, Normandy, France 6th-8th July, 2016.
    • Hermant, P., Piveteau, C., Biela, A., Bosc, D., Roignant, M., Deprez, B., & Deprez-Poulain, R. Plasma and Microsomal Esterases involvement in the Metabolism of Hydroxamic acids in two species. 2"rd Young Research Fellow Meeting of the SCT, Lille, France, 15th-17th Feb., 2016

    2014

    • Zervoudi, E., Hermant, P., Deprez-Poulain, R., & Stratikos, E. Allele-dependent activation of ERAP1 by a small molecule 8th International Workshop on Antigen Processing and Presentation, Philadelphia, USA, 10th-13th Jun, 2014.
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