Élie Besserer-Offroy

Investigating the role of APJ heterodimers in pain modulation

A large number of currently prescribed drugs target G-protein coupled receptors (GPCRs). These transmembrane proteins form the most important protein family present at the cell surface. GPCRs are involved in transducing a signal from the surrounding cellular environment into intracellular activity. Drugs targeting the same binding pocket as the endogenous ligand may have an activity similar to that of the ligand (agonist), or may block its effect (antagonists). Prescribed drugs often have side effects that could be due to a lack of specificity of these molecules. Traditionally, GPCR signaling was conceptualized with monomeric receptors, however, it is now accepted that some GPCRs are able to associate with others to form heteromeric complexes. The close relationship maintained by two GPCRs in a dimeric complex could influence the intracellular signaling events triggered by each. In this study, we propose to evaluate the activity of dimers formed by the apelin receptor and the neurotensin NTS1 receptor, or the apelin receptor and the kappa-opioid receptor. These three GPCRs are known to have powerful analgesic properties, thus we would like to evaluate the role played by these heterodimeric complexes in pain modulation. A better understanding of the role of heterodimeric complexes involving the apelin receptor would allow the development of new molecules specifically targeting these GPCR dimers. Such drugs would be more efficient, more specific, and therefore, have fewer side effects.

Development of allosteric ligands to treat pain

The treatment of chronic pain is an incredibly important medical issue. Nearly 20% of adults suffer from chronic pain on a daily basis, and unfortunately, most of the treatments available are not effective. Our team is now working on a new, promising strategy in pain relief called pepducins. Pepducins are small, cell-penetrating proteins that are designed to mimic and interact with receptors in a unique way. Rather than simply fitting into a receptor, like a key into a lock, they imbed themselves in the cell membrane, flip towards the inside of the cell, and interact with the receptor there, modifying the signals that it is sending. Although pepducins have been developed to tackle different diseases, they have not yet been studied in the context of pain. This is precisely our aim, and so, our team has designed pepducins targeting two different receptors involved in pain transmission. Our goal is therefore to study pepducin behavior both on cells and on live animals (rats). This will involve testing for analgesia (pain-relief) in acute pain models, but also in tonic andchronic pain models. All in all, this research is extremely valuable, as it may lead to new and much-needed pain-relievers.