ERAP modulators

Team

  • Team Leader: Pr Rebecca Deprez-Poulain PhD - PharmD - IUF member
  • Damien Bosc - Ass. Prof.
  • Ronan Gealageas - PostDoc
  • Paul Hermant -PhD student
  • Keguang Cheng - PostDoc
  • Florence Leroux PhD - PharmD Biochemist
  • Julie Dumont – Ass Eng

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

A primary screen has provided key modulators of these enzymes that are currently being optimized.

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.

Grants

  • 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

Poster papers

  • 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
  • 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.
TOP