Introduction
1. Development of innovative nucleosides and dinucleotides
| Scheme |  |
| Description | Nucleosides and nucleotides play a vital role in biological processes and represent a family of molecules offering a wide range of therapeutic applications not only in cancer but also in bacteria and viruses deseases. For many years, the team was interested in the synthesis of nucleoside analogs by modifying the ribosyl ring or the nucleic base, and our research has also focused on altering the internucleotide bond.
In 2015, in collaboration with pharmaceutical companies, we applied our expertise in this field to develop new molecules with antiviral properties, particularly analogs of ribavirin and remdesivir (OBC, 2022), which are molecules with broad antiviral spectrum. Inspired by methodologies developed within the team to generate amide analogs of nucleoside dimers, a program targeting amide analogs of cyclic antibacterial dinucleotides, such as c-GMP, was also conducted.
In 2021, our team was identified by the CNRS to coordinate a national research program GAVO (Generation of Original Antivirals) and to design new nucleoside molecules like AZT and Remdesivir analogs intended for evaluation against a panel of RNA viruses, including SARS-CoV-2. In collaboration with the VIROCRIB network and the MaSC platform (UVE, Marseille), the compounds are tested on families of viruses (respiratory viruses, arboviruses…), to identify potential drug candidates. We also explore new methodologies to prepare original nucleoside analogs (Synthesis 2025) |
| Collaboration(s) | Laboratoires pharmaceutiques JANSSEN Val de Reuil (France) et Beerse (Belgium)
ICOA-UMR 7311, Orléans (équipe L. Agrofoglio) IBMM -UMR 5247, Montpellier (équipe NuEP : J.J. Vasseur et S. Peyrottes) VIROCRIB (https://www.virocrib.fr/) MaSC -UVE, Marseille (platform PCVMT-F Touret) Université Paris-Saclay BIOCIS (S. Messaoudi) |
| Financial support | Laboratoires pharmaceutiques JANSSEN
Programme G.A.V.O. (Génération d’AntiViraux Originaux) – Chimie CNRS |
| Sign. Publications (2 max.) | 1. J. Org. Chem., 2016, 81 (22), 10742-10758. doi.org/10.1021/acs.joc.6b01822
2. Org. Biomol. Chem., 2022, 20, 2715. doi: 10.1039/d1ob02451e. 3. Synthesis, 2025, 57(07), 1319-1328. doi: 10.1055/s-0043-1773520.
|
| Personnels impliqués | L. Arzel ; J. Lebreton ; M. Mathé-Allainmat ; A. Tessier |
2. Innovative drugs targeting Protein-Protein interactions
In 2016, for a period of 5 years, The « Région Pays de la Loire » and its 3 Universities provided financial support for the PIRAMID project co-managed by two members of Symbiose team, S. Collet and J. Lebreton . This program has involved 12 Research teams (5 in synthesis, 2 in modelling and 5 in biology) with the goal of identifying new drug candidates for the treatment of diseases in oncology, immunology, cardiology, and in the field of anti-infectives by targeting protein-protein interactions through rational approaches.
Symbiose team is directly involved in many projects which are presented below.
2a. Chimiothérapie ciblée bloquant la recombinaison homologue via des inhibiteurs de RAD51
| Scheme |  |
| Description | DNA repair process is particularly important in maintaining genomic integrity. In proliferative disease therapies such as radiotherapy or chemotherapy, this process can restore the DNA damaged with the treatment, making cancer cells less vulnerable. Homologous recombination (HR) is one of the two cellular pathways that repair DNA double-strand breacks. HR is catalysed with Rad51 a hightly conserved protein overexpressed in a wide varieties of cancer and consequently contributing to drug resistance. That’s why Rad51 DNA-repair blockage either indirectly or directly by small molecules is relevant especially to improve response to radio- or chemotherapy treatment. In collaboration with our biologist partner at US2B in Nantes, a series of DIDS (4,4'-diisothiocyanato-2,2'-stilbene disulfonate) analogs has been developed for in vitro and in cellulo studies on the inhibition of homologous recombination by blocking RAD51. This work has led to the identification of new molecules of interest, which have been the subject of a patent application and several publications. Two molecules demonstrated HR inhibition at the micromolar level and sensitize prostate cancer (DU145) and melanoma (A375) cells to cisplatin treatment. The initial in vivo studies were supported by pre-maturation funding from SATT Ouest-Valorisation. |
| Collaboration(s) | US2B - UMR CNRS 6286, équipeNantes |
| Financial support | PIRAMID - Région Pays de la Loire & Universités ligériennes (2016-21)
Ligue contre le Cancer -CSIRGO (2023) |
| Sign. Publications (2 max.) | Patent EP18306546.5 (22.11.2018) ; WO 2020104634 A1 2020.05.28 and US 12,233,041 B2 (02/2025).
Molecules 2021, 26 (18), 5460. doi.org/10.3390/molecules26185460. Bioorg. Med. Chem. Lett. 2023, 87 : 129261doi.org/10.1016/j.bmcl.2023.129261. |
| Personnels impliqués | J. Lebreton ; M. Mathé-Allainmat, |
2b. Identification et développement de molécules antagonistes du système IL-15
| Scheme |  |
| Description
|
Cytokines are key mediators involved in the regulation of the immune response. IL-15, a cytokine discovered in 1994, belongs to the IL-2 family. Both cytokines have similar functions, such as stimulating T-cell proliferation and proliferation of T lymphocytes and NK cells. Dysregulation of the expression of these cytokines plays a pivotal role in the pathogenesis of autoimmune diseases, and elevated levels of IL-15 have been observed in inflammatory diseases such as rheumatoid arthritis, lupus, multiple sclerosis, and inflammatory bowel disease. To date, only a few low-molecular-weight molecules have been identified as potent inhibitors of IL-2 through fragment-based drug design (FBDD) approaches or chemical libraries screening.
In collaboration with the Mocka team at CRCI2NA, a virtual screening of chemical libraries targeting a specific “hot spot” at the IL-15/IL-15Rβ interface was conducted . We so identified promising compounds, which interest could be confirmed by in vitro experimental tests (binding, pStat5 activity). The selection of one of these hits, followed by its chemical optimization, led to the first molecules exhibiting nanomolar IL-15 inhibitory activity (J. Med. Chem., 2017). A second study was conducted to optimize the selectivity of IL-15 versus IL-2 (Bioorg. Med. Chem., 2021). |
| Collaboration(s) | CRCI2NA IRS-Nantes (Inserm UMR 1232 -équipe MocKa)
Laboratoire de Chimie Organique SFR QUASAV 4207 (Angers) Equipe ModES – Laboratoire CEISAM UMR CNRS 6230
|
| Financial support | PIRAMID - Région Pays de la Loire & Universités ligériennes |
| Sign. Publications (2 max.) | J. Med. Chem, 2017, 60 (14), 6249-6272, doi/10.1021/acs.jmedchem.7b00485
Bioorg. Med. Chem. 2021, 39 , 116161. doi.org/10.1016/j.bmc.2021.116161.
|
| Personnels impliqués | L. Arzel , D. Dubreuil ; J. Lebreton ; M. Mathé-Allainmat |
2c. Ciblage de l’interaction entre Protéine Rho et son facteur d’échange par des inhibiteurs innovants
| Scheme |  |
|
| Description |
|
|
| Collaboration(s) | I’institut du Thorax (Inserm UMR 1087)
CRCINA (Inserm UMR 1232 - CNRS ERL 6001) US2B – UMR CNRS 6286, Nantes. |
|
| Financial support | PIRAMID - Région Pays de la Loire & Universités ligériennes
i-Site NEXT TROPIC 3 maturation projects with SATT-Ouest Valorisation |
|
| Sign. Publications (2 max.) | 2 patents WO/2018/224563 et WO/2018/224560 | |
| Personnels impliqués | S. Collet ; J. Lebreton ; A. Tessier |
3. Anti –EGFR glycoconjugated antibody for imunotherapy
| Scheme |  |
| Description | The use of anti-EGFR Monoclonal Antibodies (MoAbs) is nowadays part of the treatment algorithm in RAS wild-type colorectal cancer, head and neck cancer since its approval by the regulation agencies. Their activity has also been demonstrated in Non-Small-Cell Lung cancer. In addition to interfering with signal transduction along the EGFR pathway, MoAbs also have demonstrated immune properties like Antibody Dependent Cell Cytotoxicity (ADCC) for Cetuximab or Complement Dependent Cytotoxicity (CDC) for Panitumumab. However, the impact of such immune functions remains unknown and, if activated in cancer patients, they are not sufficient for disease control as reflected by an absence of objective response in KRAS mutant colorectal cancer.
Over the past years, many approaches have been developed with the goal of improving the therapeutic index of anticancer agents. Numerous research efforts have concentrated on conjugating anticancer drugs with a wide spectrum of carriers: sugars, vitamins, peptides, synthetic polymers and antibody. As a general statement, the resulting carrier-drug conjugates were designed in order to allow: (1) the transport in the body of potent anticancer agents in an innocuous manner toward safe tissues, (2) the efficient recognition of malignant specificities and (3) the controlled release of the parent drug exclusively at the tumor site. Within this framework, the use of antibody–drug conjugates (ADCs) targeting specific tumor-associated antigens is by far the best-explored approach. Many of these compounds are currently evaluated in humans, including Adcetris (brentuximab vedotin) and Kadcyla (ado-Trastuzumab emtansine) which reached the market in 2011 and 2013 respectively. However, the extension of this strategy is restrained by the effective amount of such complexes (antibody/ligand) to be internalized in the cell due to a relative instability in the physiological medium and their sensibility to several enzymes present in the tumor environment. Our proposal aims at evaluating a new concept designing covalently linked immunostimulant-MoAb complexes in an “Antibody Dependant Enzyme Prodrug Therapy” strategy to elicit co-stimulatory effects in a colorectal tumor-targeted context (Scheme). This first combined immunotherapy (modified ADEPT strategy) using glycolipid immunostimulators with anti-tumor MoAbs is a promising means of tumor control and some recent outcomes strongly support this hypothesis. The goal of the project is focused on the therapeutic potential of original immune glycoconjugated-MoAb associating potent known glycosylceramide immunostimulants and available anti-EGFR MoAb: Cetuximab or Panitumumab. We thus anticipate an optimization of the immune response efficiency by a control of the therapeutic doses limiting secondary effects and counteracting RAS mutation mediated resistance to MoAbs alone. The chemical relevance of our project consists in the production of new glycoconjugated-MoAb complexes 1 by only using residues that have been already recognized to be by their own efficient and safe in previous anticancer therapeutic studies. All glycoconjugated intermediates 2-4 will be evaluated.-If data are convincing enough in preclinical models, the next objective will be to perform, in association with a major pharmaceutical company, a phase I trial in colorectal and lung cancer patients after failure of conventional therapy, including anti-EGFR MoAbs.
Expected medical potential impact of the translational research: - Glycoconjugated anti-EGFR MoAb will improve immune functions and superior tumor growth inhibition compared to non-glycosylated antibodies by enhancing ADCC and other immune-mediated effects, and bypassing the resistance provided by RAS mutations on the blocking of signal transduction. - Glycoconjugated anti-EGFR-MoAb could add another mode of action to the conventional inhibition of the EGFR pathway and will improve efficacy by a dual mode of action and could potentially circumvent resistance of RAS mutant colorectal cancer patients to anti-EGFR.
|
| Collaboration(s) | Société MERCK KGaA (Deutchland)
Inserm-UMR 1232 CNRS ERL 6001 (Institut de Recherche Santé, CRCINA-IRS) : Jacques Le Pendu. Centre René Gauducheau, Centre Régional de Lutte Contre le Cancer Nantes-Atlantique : Jean-Yves Douillard. |
| Financial support | Société MERCK serono
Projet pré-maturation SATT-Ouest valorisation Cancéropôle Grand Ouest Financement d’une thèse - réseau inter-régional transdisciplinaire Glycoouest |
| Sign. Publications (2 max.) | European Patent 2020, n°20290005.6 |
| Personnels impliqués | D. Dubreuil, M. Pipelier, V. Blot, A. Tessier ; J. Lebreton |