Peptide biotherapies - INSERM ERL1321 (Pr Dominique Bagnard)

Summary

Research interests

Over the past 15 years, the team has established a rational design process to develop Therapeutic Peptides that interfere with the dimerization and oligomerization of membrane receptors. These transmembrane receptors are the first key step for the activation of signaling pathways leading to cell migration, proliferation and differentiation. Overexpression or constitutive dimerization of these receptors are often involved in diseases such as cancers or neurological disorders. Thus, interfering peptides (called MTPs for Membrane targeting peptides), which specifically disrupt/modulate the interaction between these receptors by mimicking their transmembrane domains, are powerful molecular tools to combat these diseases.

The team conducts fundamental research for the discovery of new targets and new mechanisms of action, in order to develop innovative peptide therapeutic approaches using the MTPs strategy. For a given membrane receptor, we can initiate the design and biological validation of new MTPs by integrating an in silico design step followed by in vitro functional tests involving among others a newly automated BRET (Bioluminescence Resonance Energy Transfer) assay to verify the selectivity and specificity of the MTP for its target receptor. Thus, a major breakthrough was achieved by completing the complete screening of the contribution of transmembrane domains in receptor tyrosine kinase (RTK) dimerization. More than 10,000 interactions between RTKs were analyzed using the BRET assay to obtain a complete picture of potential interactions to target. This work continues with the development of new MTPs based on the results of this screening. This systematic approach will be conducted by defining priorities linked to medical needs and in a translational approach including industrial partnership. We also wish to extend this approach to the family of 7-transmembrane G-protein-coupled receptors (GPCRs) that offer an interesting source of new therapeutic targets.

Depending on the intended medical indication, the therapeutic potential of the MTP can then be evaluated in vivo in relevant models of the disease, while verifying the safety of the peptide compound, as was done for a MTP targeting PlexinA1 and likely to provide the first drug promoting re-myelination in the context of multiple sclerosis (Binamé et al., 2019). These general objectives will be supported by a more fundamental research activity aimed at dissecting the mechanisms of the targeted pathological processes (in particular for brain tumors and demyelinating diseases) while identifying biomarkers likely to help in the development of MTPs towards the clinic by stratifying patients and/or measuring therapeutic efficacy, using among other things brain organoids to model pathologies.

Funding

Team members

Publications

Birmpili D, Charmarké-Askar I, Spenlé C, Riché S, Pham-Van LD, Kuntzel T, Xhurxhi T, Riou A, Bonnet D, Bagnard D (2024). Fluorinated apelin-13 mediates neuroprotective effects in multiple sclerosis models. Neurobiol Dis 198:106552. doi: 10.1016/j.nbd.2024.106552.

Charmarke-Askar I, Spenlé C, Bagnard D (2024). Complementary strategies to be used in conjunction with animal models for multiple sclerosis drug discovery: adapting preclinical validation of drug candidates to the need of remyelinating strategies. Expert Opin Drug Discov 22:1-10. doi: 10.1080/17460441.2024.2382180.

Kuntzel T, Spenlé C, Pham-Van LD, Birmpili D, Riou A, Loeuillet A, Charmarke-Askar I, Bagnard D (2023). Implication of the Transmembrane Domain in the Interleukin 10 Receptor Platform Oligomerisation. Cells 12(10):1361. doi: 10.3390/cells12101361.

Birmpili D, Charmarke Askar I, Pham-Van LD, Kuntzel T, Spenlé C, Riou A, Bagnard D (2022). Toward a Combination of Biomarkers for Molecular Characterization of Multiple Sclerosis. Int J Mol Sci 23(22):14000. doi: 10.3390/ijms232214000.

Birmpili D, Charmarke Askar I, Bigaut K, Bagnard D (2022). The Translatability of Multiple Sclerosis Animal Models for Biomarkers Discovery and Their Clinical Use. Int J Mol Sci 23(19):11532. doi: 10.3390/ijms231911532.

Kuntzel T, Bagnard D (2022). Manipulating Macrophage/Microglia Polarization to Treat Glioblastoma or Multiple Sclerosis. Pharmaceutics 14(2):344. doi: 10.3390/pharmaceutics14020344.

Steindorf D, Loeuillet A, Bagnard D, Strand S, Schneider D (2022). Increased stability of the TM helix oligomer abrogates the apoptotic activity of the human Fas receptor. Biochim Biophys Acta Biomembr 1864(1):183807. doi: 10.1016/j.bbamem.2021.183807.

Varin B, Rehbinder J, Dellinger J, Heinrich C, Torzynski M, Spenlé C, Bagnard D, Zallat J (2021). Monitoring subcutaneous tumors using Mueller polarimetry: study on two types of tumors. Biomed Opt Express 12(10):6055-6065. doi: 10.1364/BOE.433754.

Binamé F, Pham-Van LD, Bagnard D (2021). Manipulating oligodendrocyte intrinsic regeneration mechanism to promote remyelination. Cell Mol Life Sci 78(13):5257-5273. doi: 10.1007/s00018-021-03852-4.

Jolivel V, Brun S, Binamé F, Benyounes J, Taleb O, Bagnard D, De Sèze J, Patte-Mensah C, Mensah-Nyagan AG (2021). Microglial Cell Morphology and Phagocytic Activity Are Critically Regulated by the Neurosteroid Allopregnanolone: A Possible Role in Neuroprotection. Cells 10(3):698. doi: 10.3390/cells10030698.

Albrecht C, Kuznetsov AS, Appert-Collin A, Dhaideh Z, Callewaert M, Bershatsky YV, Urban AS, Bocharov EV, Bagnard D, Baud S, Blaise S, Romier-Crouzet B, Efremov RG, Dauchez M, Duca L, Gueroult M, Maurice P, Bennasroune A (2020). Transmembrane Peptides as a New Strategy to Inhibit Neuraminidase-1 Activation. Front Cell Dev Biol 8:611121. doi: 10.3389/fcell.2020.611121.

Metzger-Peter K, Kremer LD, Edan G, Loureiro De Sousa P, Lamy J, Bagnard D, Mensah-Nyagan AG, Tricard T, Mathey G, Debouverie M, Berger E, Kerbrat A, Meyer N, De Seze J, Collongues N (2020). The TOTEM RRMS (Testosterone Treatment on neuroprotection and Myelin Repair in Relapsing Remitting Multiple Sclerosis) trial: study protocol for a randomized, double-blind, placebo-controlled trial. Trials 21(1):591. doi: 10.1186/s13063-020-04517-6.

Albrecht C, Appert-Collin A, Bagnard D, Blaise S, Romier-Crouzet B, Efremov RG, Sartelet H, Duca L, Maurice P, Bennasroune A (2020). Transmembrane Peptides as Inhibitors of Protein-Protein Interactions: An Efficient Strategy to Target Cancer Cells? Front Oncol 10:519. doi: 10.3389/fonc.2020.00519.

Fritz J, Lefebvre O, Fernandez A, Schmidt J, Bagnard D (2020). Prediction of Drug Efficacy in Colon Cancer Preclinical Models Using a Novel Ranking Method of Gene Expression. Cancers 12(1):149. doi: 10.3390/cancers12010149.

Gamper C, Spenlé C, Boscá S, van der Heyden M, Erhardt M, Orend G, Bagnard D, Heinlein M (2019). Functionalized Tobacco Mosaic Virus Coat Protein Monomers and Oligomers as Nanocarriers for Anti-Cancer Peptides. Cancers 11(10):1609. doi: 10.3390/cancers11101609.

Binamé F, Pham-Van LD, Spenlé C, Jolivel V, Birmpili D, Meyer LA, Jacob L, Meyer L, Mensah-Nyagan AG, Po C, Van der Heyden M, Roussel G, Bagnard D (2019). Disruption of Sema3A/Plexin-A1 inhibitory signalling in oligodendrocytes as a therapeutic strategy to promote remyelination. EMBO Mol Med 11(11):e10378. doi: 10.15252/emmm.201910378.

Ripoll M, Pierdant M, Neuberg P, Bagnard D, Wagner A, Kichler A, Remy JS (2018). Co-delivery of anti-PLK-1 siRNA and camptothecin by nanometric polydiacetylenic micelles results in a synergistic cell killing. RSC Adv 8(37):20758-20763. doi: 10.1039/c8ra03375g.

Kuchler-Bopp S, Bagnard D, Van-Der-Heyden M, Idoux-Gillet Y, Strub M, Gegout H, Lesot H, Benkirane-Jessel N, Keller L (2018). Semaphorin 3A receptor inhibitor as a novel therapeutic to promote innervation of bioengineered teeth. J Tissue Eng Regen Med 12(4):e2151-e2161. doi: 10.1002/term.2648.

Meyer LA, Kaselis A, Satkauskas S, Bagnard D (2017). Analysis of Semaphorin-Induced Growth Cone Collapse and Axon Growth Inhibition. Methods Mol Biol 1493:171-183. doi: 10.1007/978-1-4939-6448-2_12.

Meyer LA, Fritz J, Pierdant-Mancera M, Bagnard D (2016). Current drug design to target the Semaphorin/Neuropilin/Plexin complexes. Cell Adh Migr 10(6):700-708. doi: 10.1080/19336918.2016.1261785.

Jacob L, Sawma P, Garnier N, Meyer LA, Fritz J, Hussenet T, Spenlé C, Goetz J, Vermot J, Fernandez A, Baumlin N, Aci-Sèche S, Orend G, Roussel G, Crémel G, Genest M, Hubert P, Bagnard D (2016). Inhibition of PlexA1-mediated brain tumor growth and tumor-associated angiogenesis using a transmembrane domain targeting peptide. Oncotarget 7(36):57851-57865. doi: 10.18632/oncotarget.11072.

Arpel A, Gamper C, Spenlé C, Fernandez A, Jacob L, Baumlin N, Laquerriere P, Orend G, Crémel G, Bagnard D (2016). Inhibition of primary breast tumor growth and metastasis using a neuropilin-1 transmembrane domain interfering peptide. Oncotarget 7(34):54723-54732. doi: 10.18632/oncotarget.10101.

Zeniou M, Fève M, Mameri S, Dong J, Salomé C, Chen W, El-Habr EA, Bousson F, Sy M, Obszynski J, Boh A, Villa P, Assad Kahn S, Didier B, Bagnard D, Junier MP, Chneiweiss H, Haiech J, Hibert M, Kilhoffer MC (2015). Chemical Library Screening and Structure-Function Relationship Studies Identify Bisacodyl as a Potent and Selective Cytotoxic Agent Towards Quiescent Human Glioblastoma Tumor Stem-Like Cells. PLoS One 10(8):e0134793.

Leriche G, Nothisen M, Baumlin N, Muller CD, Bagnard D, Remy JS, Jacques SA, Wagner A (2015). Spiro Diorthoester (SpiDo), a Human Plasma Stable Acid-Sensitive Cleavable Linker for Lysosomal Release. Bioconjug Chem 26(8):1461-5.

Sawma P, Roth L, Blanchard C, Bagnard D, Crémel G, Bouveret E, Duneau JP, Sturgis JN, Hubert P (2014). Evidence for new homotypic and heterotypic interactions between transmembrane helices of proteins involved in receptor tyrosine kinase and neuropilin signaling. J Mol Biol 426(24):4099-4111.

Arpel A, Sawma P, Spenlé C, Fritz J, Meyer L, Garnier N, Velázquez-Quesada I, Hussenet T, Aci-Sèche S, Baumlin N, Genest M, Brasse D, Hubert P, Crémel G, Orend G, Laquerrière P, Bagnard D (2014). Transmembrane domain targeting peptide antagonizing ErbB2/Neu inhibits breast tumor growth and metastasis. Cell Rep 8(6):1714-1721.

Treinys R, Kaselis A, Jover E, Bagnard D, Šatkauskas S (2014). R-type calcium channels are crucial for semaphorin 3A-induced DRG axon growth cone collapse. PLoS One 9(7):e102357.

Fernandez A, Le Bon C, Baumlin N, Giusti F, Crémel G, Popot JL, Bagnard D (2014). In vivo characterization of the biodistribution profile of amphipol A8-35. J Membr Biol 247(9-10):1043-51.

Aci-Sèche S, Sawma P, Hubert P, Sturgis JN, Bagnard D, Jacob L, Genest M, Garnier N (2014). Transmembrane recognition of the semaphorin co-receptors neuropilin 1 and plexin A1: coarse-grained simulations. PLoS One 9(5):e97779.

Ritié L, Spenlé C, Lacroute J, Bolcato-Bellemin AL, Lefebvre O, Bole-Feysot C, Jost B, Klein A, Arnold C, Kedinger M, Bagnard D, Orend G, Simon-Assmann P (2012). Abnormal Wnt and PI3Kinase signaling in the malformed intestine of lama5 deficient mice. PLoS One 7(5):e37710.

Heng C, Lefebvre O, Klein A, Edwards MM, Simon-Assmann P, Orend G, Bagnard D (2011). Functional role of laminin α1 chain during cerebellum development. Cell Adh Migr 5(6):480-9.

Page N, Gros F, Schall N, Décossas M, Bagnard D, Briand JP, Muller S (2011). HSC70 blockade by the therapeutic peptide P140 affects autophagic processes and endogenous MHCII presentation in murine lupus. Ann Rheum Dis 70(5):837-43.

Richard D, Nguyen I, Affolter C, Meyer F, Schaaf P, Voegel JC, Bagnard D, Ogier J (2010). Polyelectrolyte multilayer-mediated gene delivery for semaphorin signaling pathway control. Small 6(21):2405-11.

Nasarre C, Roth M, Jacob L, Roth L, Koncina E, Thien A, Labourdette G, Poulet P, Hubert P, Crémel G, Roussel G, Aunis D, Bagnard D (2010). Peptide-based interference of the transmembrane domain of neuropilin-1 inhibits glioma growth in vivo. Oncogene 29(16):2381-92.

Nasarre C, Koncina E, Labourdette G, Cremel G, Roussel G, Aunis D, Bagnard D (2009). Neuropilin-2 acts as a modulator of Sema3A-dependent glioma cell migration. Cell Adh Migr 3(4):383-9.

Gonthier B, Koncina E, Satkauskas S, Perraut M, Roussel G, Aunis D, Kapfhammer JP, Bagnard D (2009). A PKC-dependent recruitment of MMP-2 controls semaphorin-3A growth-promoting effect in cortical dendrites. PLoS One 4(4):e5099.

Roth L, Koncina E, Satkauskas S, Crémel G, Aunis D, Bagnard D (2009). The many faces of semaphorins: from development to pathology. Cell Mol Life Sci 66(4):649-66.

Claudepierre T, Koncina E, Pfrieger FW, Bagnard D, Aunis D, Reber M (2008). Implication of neuropilin 2/semaphorin 3F in retinocollicular map formation. Dev Dyn 237(11):3394-403.

Koncina E, Roth L, Gonthier B, Bagnard D (2007). Role of semaphorins during axon growth and guidance. Adv Exp Med Biol 621:50-64.

Roth L, Nasarre C, Dirrig-Grosch S, Aunis D, Crémel G, Hubert P, Bagnard D (2008). Transmembrane domain interactions control biological functions of neuropilin-1. Mol Biol Cell 19(2):646-54.

Satkauskas S, Bagnard D (2007). Local protein synthesis in axonal growth cones: what is next? Cell Adh Migr 1(4):179-84.

Gonthier B, Nasarre C, Roth L, Perraut M, Thomasset N, Roussel G, Aunis D, Bagnard D (2007). Functional interaction between matrix metalloproteinase-3 and semaphorin-3C during cortical axonal growth and guidance. Cereb Cortex 17(7):1712-21.