ERAP modulators

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 also with cancers and response to cancer immunotherapy. Also, the function of these proteases and their 3D-structure are well documented. While the short term goal of the proposal is the identification of promising leads, the long term goal is the generation of novel pharmacological approaches towards the treatment of ERAP-associated human diseases based on the modulation of antigen processing and adaptive immune response with applications in autoinflammatory diseases and in cancer immunotherapy.

Team

  • Team Leader: Pr Rebecca Deprez-Poulain PhD - PharmD
  • Rodolphe Vatinel – PostDoc
  • Pierre Sierocki – PostDoc
  • Laetitia Lesire – PostDoc
  • Virgyl Camberlein – PhD student
  • Tuhina Kahn – PostDoc
  • 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; Omar Castillo - PostDoc

Collaborators

  • Pr. van Endert, U1013 INSERM, Hopital Necker. Cell biology & antigenic presentation.
  • Dr. Stratikos, Demokritos Research Center, Athens, Greece. Cell Biology & X-ray.
  • Pr. Launay, INFINITE INSERM U1286, Lille Regional Hospital, University of Lille. Immunity
  • CAPSTONE CONSORTIUM

Grants

  • ANR Grant 2020-2023
  • H2020 MSCA ITN CAPSTONE 2021-2024
  • Region Hauts de France STARTAIRR 2022
  • FRM Grant 2019-2021
  • IUF Grant 2015-2020
  • Campus France Hubert-Curien Grant 2013-2014

CAPSTONE ETN project

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

ANR ERAPIMM project

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

  • 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)

Publications

2020

  • Medve, L., Gealageas, R., Lam, B. V., Guillaume, V., Castillo-Aguilera, O., Camberlein, V., Piveteau, C., Rosell, M., Fleau, C., Warenghem, S., Charton, J., Dumont-Ryckembusch, J., Bosc, D., Leroux, F., van Endert, P., Deprez, B., & Deprez-Poulain, R. Modulators of hERAP2 discovered by High-Throughput Screening. Eur. J. Med. Chem.,2020, 211: 113053.10.1016/j.ejmech.2020.113053  HAL

2017

  • 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

Conferences

2021

  • Sierocki, P. Discovery & binding study of hERAP2 modulators identified via HTS,GP2A 2021 - 29th Annual Conference,Virtual conference,25th-27th Aug. 2021
  • Deprez-Poulain, R. Kinetic target-guided synthesis et acides hydroxamiques des outils efficaces pour la drug-discovery ciblant les metalloproteases.,CEISAM, Nantes, France,26th Mar. 2021 Invited.

2020

  • Camberlein, V., Gealageas, R., Tabey-Fleau, C., Warenghem, S., Guillaume, V., Bosc, D., Florence, L., Benoit, d., & deprez-Poulain, R. Discovery of hERAP2 inhibitors by kinetic target-guided synthesis,5th Drug Discovery Day - Conception Synthèse Evaluation et Sélection du principe actif,Lille, France,16th Dec. 2020
  • Deprez-Poulain, R., Antigen presentation and pharmacological modulation of ERAPs for autoimmune diseases, including type 1 diabetes, Live Webinar on Webex Events,16th-17th June 2020 Invited.

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

Communications

2021

  • Vatinel, R., Sierocki, P., Medve, L., Gealageas, R., Guillaume, V., Rosell, M., Warenghem, S., Leroux, F., Piveteau, C., Deprez, B., & Deprez-Poulain, R. Discovery of hERAP2 modulators via high-throughput screening,8th EFMC Young Medicinal Chemists’ Symposium, Virtual conference, 9th-10th Sept.,2021.
  • Camberlein, V., Kraupner, N., Bou Karroum, N., Lipka, E., Deprez-Poulain, R., Deprez, B., & Bosc, D. One-pot procedure for the preparation of 1,5-disubstituted 1,2,3-triazoles by in-situ generation of azides,XXVI EFMC International Symposium on Medicinal Chemistry, Virtual conference, 29th Aug. - 2nd Sept.,2021.
  • Camberlein, V., Sierocki, P., Gealageas, R., Fleau, C., Guillaume, V., Bosc, D., Lesire, L., Warenghem, S., Leroux, F., Deprez, B., & Deprez-Poulain, R. Kinetic target guided synthesis enables the discovery of the first selective nanomolar inhibitors of erap2 for personalized immuno-oncology,XXVI EFMC International Symposium on Medicinal Chemistry, Virtual conference, 29th Aug. - 2nd Sept.,2021.
  • Camberlein, V., Gealageas, R., Fleau, C., Guillaume, V., Bosc, D., Medve, L., Stratikos, E., Warenghem, S., Deprez, B., & Deprez-Poulain, R. First ERAP2 selective inhibitors by kinetic-target guided synthesis to modulate antigen presentation in cancer,56th International Conference on Medicinal Chemistry, Interfacing Chemical Biology and Drug Discovery, Virtual Event, 7th-9th July,2021.
  • Sierocki, P., Medve, L., Fleau, C., Vatinel, R., Khan, T., Gealageas, R., Rosell, M., Guillaume, V., Warenghem, S., Leroux, F., Piveteau, C., Stratikos, E., Deprez, B., & Deprez-Poulain, R. Discovery & binding study of ERAP2 modulators,56th International Conference on Medicinal Chemistry, Interfacing Chemical Biology and Drug Discovery, Virtual Event, 7th-9th July,2021.
  • Sierocki, P., Vatinel, R., Medve, L., Gealageas, R., Guillaume, V., Rosell, M., warenghem, S., Florence, l., Piveteau, C., Deprez-Poulain, R., & Benoit, D. Discovery of hERAP2 modulators via high throughput screening, 28th SCT Young Research Fellows Meeting, Paris, France, 11th-12th Feb.,2021.

2020

  • Tabey-Fleau, C., Camberlein, V., Gealageas, R., Warenghem, S., Guillaume, V., Bosc, D., Benoit, D., & deprez-Poulain, R. Discovery of hERAP 2 inhibitors by Kinetic Target guided synthesis and hit optimization,5th Drug Discovery Day - Conception Synthèse Evaluation et Sélection du principe actif, Lille, France, Dec.,16th Dec. 2020.
  • Vatinel, R., Sierocki, P., Medve, L., Gealageas, R., Guillaume, V., Rosell, M., Warenghem, S., Florence, L., Piveteau, C., Deprez-Poulain, R., & Benoit, D. Discovery of hERAP2 modulation via high-throughput screening approach 5th Drug Discovery Day - Conception Synthèse Evaluation et Sélection du principe actif, Lille, France, 16th Dec.,2020.
  • Tabey-Fleau, C., Camberlein, V., Gealageas, R., Warenghem, S., Guillaume, V., Bosc, D., Benoit, D., & deprez-Poulain, R. Discovery of hERAP 2 inhibitors by Kinetic Target guided synthesis and hit optimization,27th SCT Young Research Fellow Meeting, Caen, France, 29th-31st Janv.,2020.

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.

Prizes and awards

2020

  • 2020 Michel Delalande Prize of the Academie Nationale de Pharmacie to R. Deprez-Poulain (Dec. 2020).

2019

  • 4th Drug Discovery Day Best Oral Communciation Prize to Camberlein, V. (Dec 2019) Discovery of hERAP2 inhibitors by in situ click chemistry.  Lille, France. 

2015

  • Institut Universitaire de France, Junior Member to Deprez-Poulain, R., 2015-2020.
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