Category: Research

Structure based drug design

Structure Based Drug Design

We develop several projects related to the characterization and inhibition of molecular interactions between proteins and protein-ligand.

Based on molecular modeling studies of protein-protein or protein-ligand interactions, our first step is to design pharmacophore constraints to orient the design of putative inhibitor candidates. In collaboration with chemists, the most suitable scaffold (foldamer, chemical molecule and peptide) is selected and candidates are synthetized. Then, after purification of functional proteins, we carry out protein-protein and protein-ligand interaction studies by biophysics to evaluate the inhibitory potency of compounds.

CONTACT

Alain Chavanieu
Alain Chavanieu
Ludovic Maillard
Ludovic Maillard
Sébastien Estran
Sébastien Estran

Design of GPCR ligands

Design of GPCR ligands

Our research is focused on the conception, design and synthesis of ligands that target peptidic hormone GPCRs. More precisely we work on tufstin, cholecystokinin, bradykinin, bombesin, gastrin releasing peptide, neurotensin, ghrelin, gastrin… Our aim is to find very specific molecules that target one physiological biological activity of a given receptor and that can be developed in pre-clinical studies. These compounds can be peptides, pseudo-peptides or non-peptide moieties. They can exhibit agonist, antagonist or inverse agonist properties toward the desired receptor, depending on the expected biological activity. We also routinely synthesize biological tools useful for our biologist partners (purification of receptors, high throughput screening, radiopharmaceutical or fluorescent ligands for imaging, photoactivable probes for receptor identification, labeled N15 peptides for NMR interactions with the receptor…).

The important work in the field has allowed the identification of compound JMV 1843 that was recently commercialized (Macrilen™) as drug for the diagnosis of the growth hormone deficiency.

CONTACT

JEAN-ALAIN FEHRENTZ
JEAN-ALAIN FEHRENTZ
Jean Martinez
Jean Martinez
Séverine Denoyelle
Séverine Denoyelle
Luc Brunel
Luc Brunel
Pascal Verdier
Pascal Verdier

Design and synthesis of heterocycles for therapeutic applications

Heterocycles for therapeutic applications

Heterocycles are common structural units in marketed drugs and in medicinal chemistry due to the central role they play in modern drug design. Indeed, heterocycles are useful scaffolds that can be decorated with various substituents in order to modulate lipophilicity, polarity, and hydrogen bonding capacity of molecules. These structural modulations may lead to improved pharmacological, pharmacokinetic, toxicological, and physicochemical properties of drug candidates. Heterocycles are also routinely used as bioisosteres for a variety of functional groups in drug candidates. Therefore, heterocycles represent privileged structures in the drug discovery process.

In order to find new potential lead compounds for therapeutic applications, we develop methodologies to access and structurally modulate heterocycle scaffolds such as [1,2,4]triazoles, diazepines, thiazoles and triazole-ketopiperazines.

CONTACT

Nicolas Masurier
Nicolas Masurier
Jean Martinez
Jean Martinez
Séverine Denoyelle
Séverine Denoyelle
Laurent Gavara
Laurent Gavara
Ludovic Maillard
Ludovic Maillard
JEAN-ALAIN FEHRENTZ
JEAN-ALAIN FEHRENTZ

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

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

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