M2SV : Drugs and Molecules for Living Systems

UMR 1177 M2SV – Lille University – INSERM – Institut Pasteur de Lille

équipe molécules et systèmes vivants

Presentation

The laboratory’s mission is to design and synthesize drug candidates with an innovative mode of action, aimed at achieving clear therapeutic progress in indications where the medical need is poorly satisfied. This interdisciplinary molecular invention work is inspired by the most recent discoveries made on infectious diseases, metabolic diseases and cancer. By discovering molecules, new therapeutic solutions can be offered and the involvement of the mechanisms highlighted by biologists in the pathophysiological processes can be validated. The design and optimisation of new drugs require interdisciplinary expertise covering chemistry, physics, biology and in silico modelling. Indeed, the active ingredient of modern drugs, whether they are synthetic or biological in origin, is always defined at the molecular, or even the atomic, level. This particular molecular structure – perfected by the researchers of the unit – is the key to all the properties of the drug. It conditions its ability to cross the physical and chemical barriers between the different biophases (intestine, blood, tissues, brain, etc.) of the body, and to attain the set target. It is also key to its interaction with the intended target and the achievement of the desired effect. Beyond the therapeutic goal, molecules also serve as valuable tools that help biologists better understand how the cell and living organisms work and verify that the proposed targets for treating diseases are relevant. Researchers are working on antimicrobial resistance (AMR), viral infections (COVID-19), type 2 diabetes and NASH, certain forms of cancer and autoimmune diseases.

The Strategic Steering Committee of the laboratory is composed of the tenured researchers and is headed by Benoit Deprez.

Highlights

  • TB-Boost project : drug candidate BVL-GSK098 has entered Phase 1 clinical trials.
    From a collaboration, established in 2011 between our team, the group of A. Baulard and Bioversys, to develop ethionamide boosters for the treatment of tuberculosis, we identified and optimized powerful compounds capable of overcoming resistance to Ethionamide on multi-resistant strains. This scientific breakthrough, published in Science in March 2017, resulted in the signing of a contract with GSK for the preclinical and clinical development of this chemical series. The entry into the clinical phase of the drug candidate BVL-GSK098 was achieved in December 2020 with administration to the first healthy volunteer. The phase 2A study is scheduled for mid-2021.
  • European CAPSTONE project granted
    Our research team has been awarded a European project H2020-Marie-Curie European Training Network (call 2020- grant agreement No 954992) for the period 2021-2024. Pr Deprez-Poulain is the coordinator of this consortium composed of 10 beneficiaries, 9 partner organizations and including 7 industrials. This multidisciplinary project aims to train experts in structural biology, immunology, biochemistry, proteomics and medicinal chemistry to develop small molecules to treat autoimmune diseases and cancer, based on the modulation of endoplasmic reticulum aminopeptidases (ERAP). The 15 PhD students will be recruited in 2021.
  • COVID-19 projects :
    Our research team and U1019 unit have jointly initiated, as early as February 2020, a research work to identify antiviral compounds effective against SARS-CoV-2, the etiologic agent of COVID-19. Two approaches have been employed. The first aims to propose a drug for the clinic in less than 12 months through repositioning.  The second, longer-term strategy aims to design a novel molecule specifically to inhibit SARS-CoV-2 and all related coronaviruses.

Transversal projects

Research Group : Drugs and Molecules for treating viral infections :

  Development of new antiviral agents to fight against SARS-CoV-2 and potential emerging coronaviruses

U1177 : J. Charton (PI) ; Collaboration with l’U1019 (Dr S. Belouzard, Dr J. Dubuisson) and U1167 (Dr X. Hanoulle).

  Repositioning THERAPIDE Project

U1177: B. Deprez (PI) ; Collaboration with the U1019 and Apteeus.

Research Group : Drugs and Molecules for treating metabolic diseases, autoimmune diseases and cancer :

  TGR5 agonists in metabolic and inflammatory diseases

U1177 : J. Charton (PI) ; Collaboration with the U1011 and INIFINITE U1286.

  Hydroxamates Boosters of anti-cancer therapies PCSI SMOOTH-MM & SATTNord

U1177 : B. Deprez (PI) with D. Bosc (PI) ; Collaboration with Dr. E. De Bruyne (VUB, BE), Dr. J. Moreaux (UMR 9002), Pr. C. Abbadie (U1277), Pr W.-J. Tang (U. Chicago).

  Innovative drug discovery strategies: New chemical modalities. iSite ULNE grant

U1177 : D. Bosc (PI), Pr W.-J. Tang (U. Chicago).

  Innovative drug discovery strategies: KTGS

U1177 : Deprez-Poulain (PI) ; Collaboration with the Pr A. Hirsch (HIPS, Helmholtz Saarbrucken, GE).

  Inhibitors of Insulin Degrading Enzyme in metabolic diseases Region-FEDER CPER grant, ANR BETASTRESS, EGID/PRECIDIAB

U1177 : R. Deprez-Poulain (PI) ; Collaboration with Dr N. Hennuyer (U1011), Pr S. Lancel (U1167), Pr P. van Endert (INEM), Pr M. Solimena (IPI Helmholz Munchen, GE), Pr W.-J. Tang (U. Chicago).

  Inhibitors of aminopeptidases of the endoplasmic reticulum  for the treatment of autoimmune diseases and cancer FRM ERAP4DIAB, ANR ERAPIMM  & H2020 MSCA ETN CAPSTONE consortium

U1177 : R. Deprez-Poulain (PI) ; Collaboration with Pr P. van Endert (INEM), Pr D. Launay (INFINITE-U1286), Dr. E. Stratikos (NSCRD), CAPSTONE consortium.

Research Group : Drugs and Molecules for fighting multidrug-resistant bacteria (Anti-infectious Drug Discovery (AIDD)) :

  New chemical series with antimycobacterial activity: ANR NL4TB

U1177 : B. Villemagne (PI) ; Collaboration: Dr R. Hartkoorn, U1019 CIIL.

  Reprogramming of bioactivation pathways in M. tuberculosis: ANR SMARt-TB and OutSMARt-TB project

U1177 : N. Willand (PI) ; Collaboration : Dr A. Baulard, U1019 CIIL and Dr X. Hanoulle, U1167 ISB.

  Development of new fluoroquinolones with antimycobacterial activities: ANR Detonator

U1177: N. Willand (PI) ; Collaboration: Pr A. Aubry, U1135 APHP, Dr A. Baulard U1019, CIIL.

  IMI-Era4Tb European project

U1177 : N. Willand (PI) ; Collaboration : U1019 CIIL : https://era4tb.org/

  Development of bacterial efflux pump inhibitors: ANR EFFORT

U1177 : M. Flipo (PI) ; Collaboration : Dr R. Hartkoorn, U1019 CIIL, Pr K. M. Pos, Goethe University Frankfurt, Pr A. Frangakis, Goethe University Frankfurt, and Dr A. Vargiu, University of Cagliari.

  New bioactivation pathways for antibiotics: ProActive-2 project

U1177:  N. Willand (PI) ; Collaboration: Dr R. Hartkoorn, U1019 CIIL.

  Public/Private partnership: SMARt-Lab

U1177 : N. Willand (PI) ; Collaboration: Dr M. Bourotte and S. Lociuro, Bioversys; Dr A. Baulard and Dr. R. Hartkoorn, U1019 CIIL.

  Probing new chemical spaces, Re-Enforce & PEARL projects

U1177 : N. Willand (PI) ; Collaboration: Dr A. Baulard and Dr R. Hartkoorn, U1019 CIIL ; Prof. J.-L. Hilbert and P. Hance, Institut Charles Viollette ICV.

Members

Benoit DEPREZ
Professor, unit director
ORCID number : 0000-0002-2777-4538

Valentin GUILLAUME
Data scientist
ORCID number : 0000-0001-7920-3430

Florence LEROUX
Engineer
ORCID number : 0000-0003-0554-873X

Catherine PIVETEAU
Engineer
ORCID number : 0000-0002-3835-4619

Alexandre BIELA
Laboratory Scientist

Julie DUMONT
Assistant engineer

Adrien HERLEDAN
Assistant engineer

Olivier SONGUE
PhD student

Cyril COUTURIER
Assistant Professor
ORCID number : 0000-0002-6840-1738

Valérie LANDRY
Researcher

Sandrine WARENGHEM
Assistant engineer

Julie CHARTON
Assistant Professor
ORCID number : 0000-0001-6895-276X

Hassan HAITHAM
Post-doc

Lucile BRIER
PhD student

Fatima-Zahra CHAIBI
Master student

Rebecca DEPREZ-POULAIN
Professor

Damien BOSC
Assistant Professor
ORCID number : 0000-0002-6076-2934

Nour BOU KARROUM
Post-doc

Chau Phi DINH
Post doc

Pierre SIEROCKI
Post-doc

Rodolphe VATINEL
Post-doc

Laëticia LESIRE
Post-doc

Nicolas KRAUPNER
PhD student

Virgyl CAMBERLEIN
PhD student

Marine ANDRES
PhD student

Théo FRAZIER
Master student

Nicolas WILLAND
Professor
ORCID number : 0000-0002-0784-0462

Marion FLIPO
Assistant Professor
ORCID number : 0000-0003-2863-5721

Baptiste VILLEMAGNE
MCU
ORCID number : 0000-0002-8416-5253

Aurore DRENEAU
Post-doc

Léo FAÏON
Post-doc

Bruna GIOIA
Post-doc

Mathieu MAINGOT
Post-doc

Salia TANGARA
Post-doc

Anaïs VIEIRA-DA-CRUZ
Post-doc

Maxime EVEQUE
Research engineer

Kévin ANTRAYGUES
PhD student

Nina COMPAGNE
PhD student

Théo HATTABI
PhD student

Francesca RUGGIERI
PhD student

Hugo SCHERER
Master student

Nathalie DEKEYNE
Management assistant

Céline LENGLART
Assistant engineer – Safety and risk prevention assistant

Imen KHATA
Student

Publications

Hoguet V., Lasalle M., Maingot M., Dequirez G., Boulahjar R., Leroux F., Piveteau C., Herledan A., Biela A., Dumont J., Chávez-Talavera O., Belloy L., Duplan I., Hennuyer N., Butruille L., Lestavel S., Sevin E., Culot M., Gosselet F., Staels B., Deprez B., Tailleux A., Charton J.
Beyond the Rule of 5: Impact of PEGylation with Various Polymer Sizes on Pharmacokinetic Properties, Structure–Properties Relationships of mPEGylated Small Agonists of TGR5 Receptor.
Journal of Medicinal Chemistry, 2021, in press.

Bosc, D., Camberlein, V., Gealageas, R., Castillo-Aguilera, O., Deprez, B., & Deprez-Poulain, R.
Kinetic Target-Guided Synthesis: reaching the age of maturity.
J. Med. Chem.,2020, 63(8): 3817–3833; 10.1021/acs.jmedchem.9b01183.

Montaigne, D., Marechal, X., Modine, T., Coisne, A., Mouton, S., Fayad, G., Ninni, S., Klein, C., Ortmans, S., Seunes, C., Potelle, C., Berthier, A., Gheeraert, C., Piveteau, C., Deprez-Poulain, R., Eeckhoute, J., Duez, H., Lacroix, D., Deprez, B., Jegou, B., Koussa, M., Edme, J. L., Lefebvre, P., & Staels, B.
Daytime variation of perioperative myocardial injury in cardiac surgery and its prevention by Rev-Erbalpha antagonism: a single-centre propensity-matched cohort study and a randomised study.
The Lancet,2018, 391(10115): 59–69.10.1016/s0140-6736(17)32132-3.

Guieu, B ; Jourdan, JP ; Dreneau, A ; Willand, N ; Rochais, C ; Dallemagne, P.
Desirable drug-drug interactions or when a matter of concern becomes a renewed therapeutic strategy.
Drug Discov Today, 2020, article in press. 10.1016/j.drudis.2020.11.026.

Faïon L., Djaout K., Frita R., Pintiala C., Cantrelle F. X., Moune M., Vandeputte A., Bourbiaux K., Piveteau C., Herledan A., Biela A., Leroux F., Kremer L., Blaise M., Tanina A., Wintjens R., Hanoulle X., Déprez B., Willand N., Baulard A. R., Flipo M.
Discovery of the first Mycobacterium tuberculosis MabA (FabG1) inhibitors through a fragment-based screening.
Eur J Med Chem, 2020, vol 200, p112440. 10.1016/j.ejmech.2020.112440.

Keywords

Drugs ; Metalloprotease ; CAPSTONE-ETN ; Inhibitors ; KTGS ; ERAP ; IDE ; Macrocycles ; Chemical probes ; Antibiotics ; Anti-infective agents ; Transcription factors ; Chemical biology ; Medicinal chemistry ; Privileged structures ; AMR ; COVID-19 : SARS-CoV-2 ; Antiviral

Team contact

Benoit Deprez
Professor at Lille University

benoit.deprez@univ-lille.fr
03 20 96 40 24