Author: mbelev

Luc Brunel

Luc Brunel

LUC BRUNEL
CNRS EnGIneer

Luc BRUNEL graduated from a DEA in heterocycle chemistry, polymers and catalysis obtained at the University of Montpellier in 1997. After several experiences in the private sector, since 2003 he has been working as a CNRS engineer in biomolecule development.

He works on both the SynBio3 platform providing biomolecules of biological interest and pharmaceuticals, as responsible for syntheses and purifications in large quantities, but also within the research team of the laboratory to carry out certain precursor projects.

Luc possesses very solid skills in the fields of peptide synthesis in solution and solid support as well as a 15-year expertise in the implementation and development of peptide purification on preparative HPLC.

Luc obtained the CNRS Crystal medal in 2015.

Contact:
luc.brunel@umontpellier.fr
0033411759611

5 major publications :

In Vivo Stabilization of a Gastrin-Releasing Peptide Receptor Antagonist Enhances PET Imaging and Radionuclide Therapy of Prostate Cancer in Preclinical Studies. Chatalic KL, Konijnenberg M, Nonnekens J, de Blois E, Hoeben S, de Ridder C, Brunel L, Fehrentz JA, Martinez J, van Gent DC, Nock BA, Maina T, van Weerden WM, de Jong M. Theranostics. 2016 Jan 1;6(1):104-17. doi: 10.7150/thno.13580. eCollection 2016. 

Gastrin releasing peptide receptor-directed radioligands based on a bombesin antagonist: synthesis, (111)in-labeling, and preclinical profile. Marsouvanidis PJ, Nock BA, Hajjaj B, Fehrentz JA, Brunel L, M’Kadmi C, van der Graaf L, Krenning EP, Maina T, Martinez J, de Jong M. J Med Chem. 2013 Mar 28;56(6):2374-84. doi: 10.1021/jm301692p. Epub 2013 Mar 8.

An innovative strategy for sulfopeptides analysis using MALDI-TOF MS reflectron positive ion mode. Cantel S, Brunel L, Ohara K, Enjalbal C, Martinez J, Vasseur JJ, Smietana M. Proteomics. 2012 Aug;12(14):2247-57. doi: 10.1002/pmic.201100525.

The 1,2,4-triazole as a scaffold for the design of ghrelin receptor ligands: development of JMV 2959, a potent antagonist. Moulin A, Brunel L, Boeglin D, Demange L, Ryan J, M’Kadmi C, Denoyelle S, Martinez J, Fehrentz JA. Amino Acids. 2013 Feb;44(2):301-14. doi: 10.1007/s00726-012-1355-2. Epub 2012 Jul 14. Review.

Synthesis of peptide alcohols on the basis of an O-N acyl-transfer reaction. Tailhades J, Gidel MA, Grossi B, Lécaillon J, Brunel L, Subra G, Martinez J, Amblard M. Angew Chem Int Ed Engl. 2010;49(1):117-20. doi: 10.1002/anie.200904276

Design, structural and functional studies of folded oligomers

Folded oligomers for biomedical applications and catalysis

Our group synthesizes stapled peptides and pseudopeptide oligomers constructed from constrained β- and γ-amino acids or dipeptide mimetics able to adopt stable and predictable helical and ribbon conformations. Due to their well-defined secondary structure and their resistance to enzyme degradation, stapled peptides and foldamers are used for various biological applications, in particular for the development of efficient vectors for drug delivery, antimicrobials, inhibitors of protein-protein interactions and the targeting of the mannose 6-phosphate receptor for non-invasive cancer therapy. Bio-inspired foldamer catalysts built on heterocyclic γ-peptide scaffolds are also currently developed.

Synthesis and structural analysis of foldamers

We synthesize and characterize various homo- and hetero-oligomers using the ABOC, ATC residues which are constrained β- and γ-building blocks respectively, and Agl-AA dipeptide mimics. Depending on the sequence, we obtained different architectures, from various helices to ribbons.

Numerous techniques, i.e. CD, FTIR and NMR spectroscopies, X-ray diffraction and DFT calculations are combined to characterize the three dimensional structure of the various oligomers.

 Interaction with proteins

Stapled peptides and foldamers are currently evaluated for their ability to regulate physiological processes inhibiting protein-protein interactions, proteins aggregation in various pathological context such as cancers or Alzheimer disease as example. We also developed original glycofoldamers targeting the mannose 6-phosphate receptor overexpressed in prostate cancer cell lines and tissues.

Development of antimicrobial foldamers

A bioactive analogue of gramicidin S was successfully designed using an ATC building block as a turn inducer. The NMR solution structure of the analogue adopted an antiparallel β-pleated sheet conformation similar to that of the natural compound. The hybrid α,γ-cyclopeptide exhibited significant reduced hemotoxicity compared to gramicidin S, while maintaining strong antibacterial activity [1-3]. New highly selective sequences exhibiting strong antimicrobial activities are currently developed.

CONTACT

Muriel Amblard
Muriel Amblard
Lubomir Vezenkov
Lubomir Vezenkov
Baptiste Legrand
Baptiste Legrand
Jean Martinez
Jean Martinez
Ludovic Maillard
Ludovic Maillard
Luc Brunel
Luc Brunel

Enzyme inhibitors

Enzyme inhibitors

Several projects in medicinal chemistry deal with enzyme inhibition. Enzymes play central roles in all life processes and in some circumstances, their inhibition can help resolve pathological situations. In most diseases, if not all, it is possible to propose at least one enzyme as a potential target, and many drugs are enzyme inhibitors. Enzymes could be human enzymes that can be inhibited to treat various diseases as cardio-vascular, inflammatory, cancer and neurological diseases. Enzymes can also be exogenous ones that are essential for the life of deadly virus, bacteria or parasites.

We have a long time experience in the design of enzyme inhibitors and we are currently investigating the following medicinal targets:

– NO Synthases

– Metallo-β-lactamases (MBL) and the bacterial resistance to β-lactam antibiotics

– HslVU, a proteasome-like complex present in the mitochondria of Trypanosomatids

– Cancers with overexpression of the lysosomal Cathepsin D (CathD)

Kallikrein inhibitors

– New antimelanoma agents

CONTACT

JEAN-FRANÇOIS HERNANDEZ
JEAN-FRANÇOIS HERNANDEZ
Ludovic Maillard
Ludovic Maillard
Laurent Gavara
Laurent Gavara
Vincent Lisowski
Vincent Lisowski
Jean Martinez
Jean Martinez
Nicolas Masurier
Nicolas Masurier

Nicolas Masurier

Nicolas Masurier

Nicolas masurier
Professor, Faculty of Pharmacy, Montpellier University

Nicolas Masurier was born in Yvetôt (France) in 1977. He first received his PharmD degree in 2003, before he obtained his PhD in 2006 from the University of Rouen (France) under the supervision of Prof. O. Lafont, working on the synthesis of β-cyclodextrin derivatives with hydrolytic activity against organophosphorous neurotoxics. Then, he moved to the University of Clermont-Ferrand (France) in the group of Pr. J.C. Teulade as an assistant-lecturer and worked on heterocyclic derivatives as tyrosine kinase inhibitors. He is currently professor in medicinal chemistry at the Faculty of Pharmacy of Montpellier. He worked at the Institut des Biomolécules Max Mousseron (IBMM), where his current research interests focus on the design, the preparation of new anticancer agents and kallikrein inhibitors.

Contact:
nicolas.masurier@umontpellier.fr
+33 411759642

5 major publications :

V. Bellet, L. Lichon, D. P. Arama, A. Gallud, V. Lisowski, L. T. Maillard, M. Garcia, J. Martinez, N. Masurier, Imidazopyridine-fused [1,3]-diazepinones Part 2: Structure-Activity Relationships and antiproliferative activity against melanoma cells, Eur. J. Med. Chem., 2017, 125, 1225-34

D. P. Arama, F. Soualmia, V. Lisowski, J.-F. Longevial, E Bosc, L. T. Maillard, J. Martinez, N. Masurier, C. El Amri, Pyrido-imidazodiazepinones as a new class of reversible inhibitors of human kallikrein 7, Eur. J. Med. Chem., 2015, 93, 202-213

A. Gallud, O. Vaillant, L.T. Maillard, D.P. Arama, J. Dubois, V. Lisowski, M. Garcia, J. Martinez, N. Masurier, Imidazopyridine-fused [1,3]-diazepinones: Synthesis and antiproliferative activity, Eur. J. Med. Chem., 2014, 75, 382-390

N. Masurier, R. Aruta, V. Gaumet, S. Denoyelle, E. Moreau, V. Lisowski, J. Martinez, L. T. Maillard, Selective C-Acylation of 2-Aminoimidazo[1,2-a]pyridine: Application to the Synthesis of Imidazopyridine-Fused [1,3]Diazepinones, J. Org. Chem., 2012, 77 (7), 3679-3685

N. Masurier, P. Zajdel, P. Verdié, M. Pawlowski, M. Amblard, J. Martinez, G. Subra, A new highly versatile handle for chemistry on solid support: the Pipecolic linker – Part 2, Chem. Eur. J., 2012, 18 (37), 11536-11540

Pascal Verdié

Pascal Verdier
Research Engineer, University of Montpellier

Pascal Verdié, a chemical engineer from the Ecole Nationale Supérieure de Chimie of Montpellier, France, performed a PhD program in Chemistry and Biology Sciences for Health, Montpellier  University, which he graduated from in 2005. He worked on the development of selective ligands for the α-MSH MC1 receptor by the means of a huge program of peptide and combinatorial chemistry.

Pascal received a Research Associate position at Montpellier University since 2005. He’s in charge of the SynBio3 platform dedicated to assist the development of research programs in life science providing biomolecules and polymers of biological and pharmaceutical interest. He succeeded in obtaining the IBISA label since January 2013 and in achieving ISO 9001 certification in 2015.

Contact:
pascal.verdier@umontpellier.fr
0033411759612

5 major publications :

  1. «Systemic Delivery of Tumor-Targeted Bax-Derived Membrane-Active Peptides for the Treatment of Melanoma Tumors in aHumanized SCID Mouse Model» A Karageorgis, M Claron, R Jugé, C Aspord, F Thoreau, C Leloup, J Kucharczak, J Plumas, M Henry, A Hurbin, P Verdié, J Martinez, G Subra, P Dumy, D Boturyn, A Aouacheria, and JL Coll1. Molecular Therapy, Molecular Therapy, 2017, 25, 2.
  2. «Sol-gel synthesis of collagen-inspired peptide hydrogel», Echalier, S. Jebors, G. Laconde, L. Brunel, P. Verdie, L. Causse, A. Bethry, B. Legrand, H. Van Den Berghe, X. Garric, D. Noe, J. Martinez, A. Mehdi and G. Subra, Materials Today, 2017, 20, 2.
  3. «Pharmacological and Biochemical Characterization of TLQP-21 Activation of a Binding Site on CHO» Molteni, L. Rizzi1, E. Bresciani1, R. Possenti, P. Petrocchi Passeri, C. Ghè, G. Muccioli, J-A Fehrentz, P. Verdié, J. Martinez, R.J. Omeljaniuk, G. Biagini, A. Binda, I. Rivolta, V. Locatelli1 and A. Torsello, Frontiers in Pharmacology, 2017, 8.
  4. «Agonism, antagonism and inverse agonism bias at the Ghrelin receptor signaling» C M’Kadmi, J-P Leyris, L Onfroy, C Galés, A Saulière¶, D Gagne, M Damian, S Mary, M Maingot, S Denoyelle, P Verdié, J-A Fehrentz, J Martinez, J-L Banères, J Marie Journal of biological Chemistry, 2015, 290(45), 27021-27039.
  5. «Ghrelin Receptor Ligands: Design and Synthesis of Pseudopeptides and Peptidomimetics » Moulin, A. Brunel, L. Verdie, P. Gavara, L. Martinez, J and Fehrentz, J-A. Current Chemical Biology, 2014, 7 (3), 254-270.

Vectorization & targeting

Vectorization and targeting

A lot of potential drugs are ineffective because of their inability to cross certain biological membranes, such as the lipid bilayer or the blood brain barrier. Once inside the cell, those compounds often have to find a local address, also known as cell compartment, but unfortunately often they will lose their way and find themselves trapped in the ‘’wrong neighborhoods’’ (cell organelles). In the same time most of the anti-cancer drugs have devastating side effects due to the fact that they target equally healthy and tumour cell. For all those reasons the terms – ‘’Vectorization, targeting and drug delivery’’ are key words in modern medicinal chemistry. In our group we actively pursue the development of cell penetrating and cell targeting compounds based on peptides, foldamers and anti-bodies. These vectors are used to send bioactive compounds, such as anti-cancer drugs, to a preferred cellular compartment or to target a certain organ or cell type in the living species.

CONTACT

Muriel Amblard
Muriel Amblard
Lubomir Vezenkov portrait
Lubomir Vezenkov
Vincent Lisowski
Vincent Lisowski
Baptiste Legrand
Baptiste Legrand
Ludovic Maillard
Ludovic Maillard
Jean Martinez
Jean Martinez

Laurent Gavara

Laurent Gavara
associate professor, ENSM

Laurent Gavara completed his M. Sci. in 2005 in Montpellier and pursued his graduate studies under the supervision of Pr. Jean-Pierre Hénichart and Pr. Benoit Rigo at the University of Lille, where he received his Ph.D. in 2008. He conducted a first postdoctoral work for 2 years in Clermont-Ferrand in the Pascal Moreau group and then moved to a second postdoctoral position for 1 year in Fort Worth, US, with the Pr. Jean-Luc Montchamp. In 2012, he joined the group of Muriel Amblard at the faculty of pharmacy of Montpellier as research fellow. One year later, he reached an associate professor position in the same group. His research interests are focused on the design and the synthesis of small heterocyclic molecules. He is currently working to fight the bacterial resistance thank to the inhibition of key bacterial enzymes.

Contact:

laurent.gavara@umontpellier.fr

+33 (0)4 11 75 96 03

5 major publications :

L. Sevaille, L. Gavara, C. Bebrone, F. De Luca, L. Nauton, M. Achard, P. Mercuri, S. Tanfoni, L. Borgianni, C. Guyon, P. Lonjon, G. Turan-Zitouni, J. Dzieciolowski, K. Becker, L. Bénard, C. Condon, L. Maillard, J. Martinez, J.-M. Frère, O. Dideberg, M. Galleni, J.-D. Docquier, J.-F. Hernandez, 1,2,4-Triazole-3-thione compounds as inhibitors of di-zinc metallo-β-lactamases. ChemMedChem. 2017 just accepted

M. Damian, S. Mary, M. Maingot, C. M’Kadmi, D. Gagne, J.-P. Leyris, S. Denoyelle, G. Gaibelet, L. Gavara, M. Garcia de Souza Costa, D. Perahia, E. Trinquet, B. Mouillac, S. Galandrin, C. Galès, J.-A. Fehrentz, N. Floquet, J. Martinez, J. Marie, J.-L. Baneres, Ghrelin receptor conformational dynamics regulate the transition from a preassembled to an active receptor:Gq complex. Proc. Natl. Acad. Sci. 2015, 5, 1601

F. Gelat, C. Lacomme, O. Berger, L. Gavara, J.-L. Montchamp, Synthesis of (phosphonomethyl)phosphinate pyrophosphate analogues via the phospha-Claisen condensation. Org. Biomol. Chem. 2015, 13, 825

V. Suchaud, L. Gavara, F. Giraud, L. Nauton, V. Théry, F. Anizon, P. Moreau, Synthesis of pyrazolo[4,3-a]phenanthridines, a new scaffold for Pim kinase inhibition. Bioorg. Med. Chem. 2014, 22, 4704

V. Suchaud, L. Gavara, E. Saugues, Nauton, V. Théry, F. Anizon, P. Moreau, Identification of 1,6-dihydropyrazolo[4,3-c]carbazoles and 3,6-dihydropyrazolo[3,4-c]carbazoles as new Pim kinase inhibitors. Bioorg. Med. Chem. 2013, 21, 4102

Muriel Amblard

MURIEL AMBLARD
Senior researcher, CNRS MONTPELLIER

Dr Muriel AMBLARD obtained her PhD in Organic Chemistry at the University of Montpellier under the supervision of Prof Jean Martinez in 1991. She joined the group of Dr Paul Anderson at Merck Sharp & Dohm in West point (Pennsylvania, USA) as a post-doctoral fellow. In 1996, she obtained a position at the Laboratory of Amino Acid Peptide and Protein in Montpellier as a CNRS researcher. She became a CNRS senior researcher and a team leader at the Institute of Biomolecules Max Mousseron in 2007. Her research interests are mainly at the interface of chemistry, biology and analysis. She developed a number of potent receptor agonists and antagonists of several peptide hormones. Related to medicinal chemistry programs, she developed new multifunctional scaffolds and focused on the design and synthesis of small molecules (diazepinones, spiroimidazolidinones, constraint dipeptide mimics) by combinatorial chemistry on solid support.

Her recent work focuses on the design and synthesis of constrained β-amino acid and dipeptide mimic oligomers as highly predictable and stable helical molecular architectures (Foldamers) applied to 1) the identification of cell penetrating compounds for the delivery of bioactive compounds inside the cells and 2) inhibitors of protein/protein interactions.

Another part of her research is devoted to the development of (1) new methodologies in peptide synthesis (the use of an O-N acyl transfer reaction for the synthesis of cyclic peptides without epimerization, new strategy for the synthesis of peptides alcohols on solid support, synthesis of stapled peptides ans peptide-polymers….) and (2) peptide-based biopolymers by new approaches relying on bottom up polymerisation of peptide-activated monomer.

Muriel is co-author of over 85 papers, 5 book chapters and 7 patents.

5 major publications :

Paramelle, G. Subra, L. Vezenkov, M. Maynadier, C. André, C. Enjalbal, M. Calmès, M. Garcia, J. Martinez, M. Amblard.A straightforward approach for cellular uptake quantification. Angew. Chem. Int. Ed. 201049, 8240-8243.

Legrand, C. André, E. Wenger, C. Didierjean, M C. Averlant-Petit, J. Martinez, M. Calmes, M. Amblard.Robust Helix Formation in a New Family of oligoureas based on a Constrained Bicyclic Building Block, Angew. Chem. Int. Ed., 2012, 51, 11267-11270

Legrand, C. André, L. Moulat, E. Wenger, C. Didierjean, E. Aubert, M C. Averlant-Petit, J. Martinez, M. Calmes, M. Amblard.Unprecedented Chain-Length Dependent Conformational Conversion Between 11/9 and 18/16 Helix inα/β-Hybrid Peptides. Angew. Chem. Int. Ed., 2014, 53, 13131-13135.

Martin, B. Legrand, L. L. Vezenkov, M. Berthet, G. Subra, M. Calmès, J.L. Bantignies, J. Martinez, M. Amblard. Turning peptide sequences into ribbon foldamers via a straightforward multi-cyclization reaction. Angew. Chem. Int. Ed., 2015, 54, 13966 –13970

Legrand, C. André, L. Moula, C. Didierjean, P. Hermet, J.L. Bantignies, J. Martinez, M. Amblard, M. Calmès, 12/14/14-Helix Formation in 2:1 α/β-Hybrid Peptides Containing Bicyclo[2.2.2]octane Ring Constraints, Chemistry: a European Journal, 2016, 22,11986 –11990

Contact:
muriel.amblard@umontpellier.fr
0033411759605

LEGOGEL

LEGOGEL
A 'Lego'-like method to access multifunctional hydrogels for mesenchymal stem cell-based cartilage repair

Funding: ANR-16-CE18-0003-01
October 2016- September 2019

The LEGOGEL multidisciplinary project combines peptide chemistry and sol-gel inorganic polymerization to provide multifunctional hydrogels for full-thickness cartilage lesion repair using mesenchymal stem cells (MSC).

Treatment of cartilage injuries remains one of the most difficult challenges in regenerative medicine. Mesenchymal stem cell (MSC)-based therapies represent one possible innovative strategy. It is highly important that MSC will be associated with a support, to put the cells directly into the lesion to be repaired but also to avoid dissemination at the time of implantation. The support can be a scaffold shaped to fit the cartilage defect or a liquid that can be injected and can rapidly turn into a gel to fill the lesion. LEGOGEL is a multidisciplinary project aiming at designing cell therapy strategies for osteo-articular diseases.

Legogel Project

LEGOGEL aims at establishing a ground-breaking method to build modular and multifunctional hydrogels whose synthesis was too complex to be envisioned by existing methods. LEGOGEL relies on original ‘hybrid’ bioorganic-inorganic building blocks (peptides, biopolymers, dyes…) bearing alcoxysilane groups. Hydrolysis and condensation of these groups lead to the formation of a covalent hydrogel network. Interestingly, this sol-gel process occurs in water in physiological conditions, without the use of chemical cross-linkers, toxic reagents or catalysts. It is thus compatible with biomolecules (ligands, growth factors…) and the presence of cells. Moreover, the mixture of blocks is first obtained as a colloidal solution that can be either injected, or 3D-printed before complete gelation to get porous scaffolds. Taking advantage of this innovative ‘lego-like’ bottom-up approach, the complexity of extracellular matrices (ECM) composed of a huge variety of biological components, could be mimicked. Any type of bioactive peptide, biopolymer, dye or contrast agent can be combined in appropriate ratio to yield covalent hydrogel. Of course, any other component (as growth factors) can be added during the gel formation, in a non-covalent way.

Specific objectives of LEGOGEL project

  1. The first goal will be the synthesis of the different hybrid blocks (i.e. the ‘lego parts’). Bioactive peptide promoting cell migration and colonization, biopolymers (growth factors) and contrast agents will be specifically silylated. The synthesis of hybrid bioactive peptides is already mastered by the partners but the introduction of silyl groups on proteins is a challenge that will be tackled.
  2. The second objective will be to obtain multifunctional hydrogels whose biological and physicochemical properties (stiffness, porosity, degradability…) will be suitable for cell-based engineering. The obtainment of hydrogel substrates from liquid solution will be studied. The most challenging work will be the control of gelation conditions to transfer the soft polymerization method on the 3D printer for the biofabrication of cell-seeded porous scaffolds. If required, Peptide sequences sensitives to ECM degradation enzymes will be incorporated to tune the degradation rate of the matrix and to release the differentiation factors to induce the lineage commitment.

    3D printer used for the project
  3. The third objective will be to obtain optimized hydrogel substrates promoting in vitro and in vivo MSC colonization and differentiation into chondrocytes or osteoblasts. Different composition of hydrogels, containing differentiation factors tailored to mimic specific cartilage and subchondral bone environments will be assayed to obtain the ‘ideal’ substrate. It will be either 3D-printed as a scaffold or used as an injectable hydrogel. Ultimately, the scaffold will present a bilayer membrane composed of TGFβ3- hyaluronic acid upper layer to induce differentiation of MSCs into chondrocytes and secretion of the cartilage ECM; and BMP2-hydroxyapatite-collagen lower layer to favor the differentiation of MSC into osteoblasts.

THE TEAM

Gilles Subra
Ahmad Mehdi
AHMAD MEHDI
Laurine Valot
LAURINE VALOT
MM
MARIE MAUMUS
Luc Brunel
LUC BRUNEL
DANIÈLE NOËL
DANIÈLE NOËL
Pascal Verdier

PASCAL VERDIÉ

Peptide-based polymers and materials

Peptide-based polymers and materials

With their outstanding range of structures, structural and biological activities, peptides are highly attractive molecules to give a tailored function to an existing material but also to design innovative materials with unprecedented properties. Existing approaches to functionalise materials with biomolecules mostly relies on post-modification using conjugation chemistry (e.g. click reactions, activated esters). On the contrary, we envisioned innovative bottom-up approaches based on peptide building-blocks bearing functions for polymerisation or condensation. We investigated organic polymerisation using peptides bearing N-carboxyanhydride (NCA) moieties or lactame rings but also inorganic polymerisation methods, using sol-gel process relying on hydroxysilane-derivatized peptides.

Applications are numerous and some of them are currently investigated thought founded programs and collaborations :

• The functionalization of medical devices and dressing with wound-healing and/or antibacterial peptides and the design of smart ‘communicant’ dressings using RFID technology.
• The synthesis of multi-ligands nanoparticles for cancer treatment and imaging.
• The synthesis of polymers for cell targeting and vectorization.
• The design of biomimetic hydrogels for cell-based therapies that can be printed as 3D scaffolds.
From a fundamental point of view, the self-assembly of hybrid peptides is also studied for the design of new nanostructured materials.

CONTACT

Gilles Subra
Gilles Subra
Pascal Verdier
Pascal Verdier
Jean Martinez
Jean Martinez
Muriel Amblard
Muriel Amblard
Lubomir Vezenkov portrait
Lubomir Vezenkov