Chemical biology and medicinal chemistry

Our research in

Chemical biology &
medicinal chemistry

FROM PROTEIN SURFACE RECOGNITION TO PEPTIDE THERAPEUTICS

 

Peptides are useful molecules to interfere with biomolecular interactions, investigate biological processes and develop new modalities for therapeutic applications. In the group, we are combining peptidomimetic and foldamer chemistries, structure-guided design and chemical biology to develop effective ligands against targets of various therapeutic interest (receptor ligands, disruptors of protein-protein interactions). In particular, we are interested in approaches to constrain peptides as they may yield compounds with unusual activity profiles including improved binding, higher resistance to degradation by proteases, and cell permeability compared with unconstrained peptides.

Figure : Effective mimicry of GLP-1 using a foldamer-based approach that consists in replacing a α-helical peptide portion by a oligourea insert (green).

Foldamers to target protein surfaces and improve bioactive peptides

 

Our ability to interface foldamers with α-eptides opens enticing opportunities for mimicking biologically active peptides and addressing some of their current limitations including stability in biological fluids (Pasco et al. in Comprehensive Supramolecular Chemistry II, 2017). However, only few unnatural helical backbone have been shown to effectively mimic biologically active peptides (e.g. for targeting protein-protein interactions or activating receptors). In 2019, we demonstrated (Nat Commun 2019, Chem Sci 2019) that peptide-oligourea helices can produce mimics of Class-B GPCR ligands with increased resistance to proteolytic degradation and prolonged duration of action in vivo. Towards the goal of developing new modalities targeted to specific proteins, we propose an integrated approach featuring combination of peptidomimetic and foldamer chemistries, structure-guided design and chemical biology to enhance the properties of biological peptides including cell uptake, and develop new inhibitors as well as molecular probes to study the consequences of target engagement in cells. One specific objective in this project is to gain details at atomic resolution of the interactions between chimeric helices and the surface of target proteins and identify general principles to guide the design of peptide/oligourea-based ligands.

Funded by :

Host defense peptide mimics and Cell Penetrating Foldamers (CPFs)

 

To be developped

Funded by :

Figure :

Antibacterial peptides targeting bacterial machinery : protein synthesis and DNA replication

 

To be developped

Funded by :