ICCF - COM Peptoid – Modulators of Protein-Protein Interactions and biomimetic architectures

Model of the interaction of the PolyProline I type helix of an α-peptoid (left) and an arylopeptoid oligomer (right) with the hydrophobic groove of the anti-apoptotic protein Bcl-xL

Protein-protein interactions (PPIs) play a major role at all levels of cellular functioning, which makes them extremely interesting therapeutic targets. However, the identification of potent inhibitors able to target interactions involving big shallow surfaces (> 800Ų) is still a challenge. PPI inhibitors could be designed by mimicking hot segments involved in the PPIs. Peptoids (i.e. oligomers of N-substituted glycine) are a promising class of peptidomimetics to reach this challenge. These pseudo-peptides have numerous advantages compared to peptide parents, notably their access (easy synthesis with huge chemical diversity) and their behaviour in a biological environment (protease resistant – better biodisponibility).

The PEPTOID group research work is devoted to the design, the synthesis and the study of foldameric properties of α-peptoid and related compounds for molecular recognition applications. Mimics of the helical BH3-domain of pro-apoptotic peptides were designed to inhibit the anti-apoptotic effect of Bcl-xl and Mcl-1 proteins. Indeed, it has been shown that it is crucial to co-inhibit these two proteins to induce the death of chemo-resistant tumor cells in certain cancers. A first family of peptidomimetic oligomers mimicking a pro-apoptotic peptide has been designed and evaluated by NMR in presence of Mcl-1 or Bcl-xL (CRMN, Lyon). Significant interactions with the hydrophobic groove of both proteins have been observed. The ability of this first family to restore apoptosis of ovarian tumor cells is currently evaluated (BioTICLA, Caen). The first results are promising and molecular modelling studies started (Molecular modelling platform ICCF) in order to better understand the peptidomimetic-protein interactions involved.