Research project: Targeting of EG-VEGF protein through structural drug-designed screening to inhibit its proangiogenic effects in inflammatory diseases
Supervisor: Ass. Prof. Mohamed Benharouga
Lab: BioSanté (Biology and Biotechnology for Heath, https://biosante-lab.fr/en), MAB2 team
Chronic inflammatory diseases are a major public health issue representing the third leading cause of death in France just after cardiovascular diseases and cancer. One example is cystic fibrosis (CF), a genetic pulmonary disease causing progressive and lethal damage to the lungs. A hallmark of this disease is the long–standing bronchial inflammation that contributes to its pathogenicity. The local inflammation in the CF lungs is controlled by inflammatory mediators and growth factors. Those factors include the endocrine gland derived–vascular endothelial growth factor (EG–VEGF) and its receptors PROKR1 and PROKR2. Herein, the main objective of the project is to block the EG–VEGF protein using chemical molecules that will specifically antagonize its interaction with its receptors. Using EG–VEGF’s tridimensional structure, we identified 330 chemical molecules as a potential ligand antagonist. To evaluate their inhibitory effects, we generated two cell lines (BHK–R1 and BHK–R2) stably expressing PROKR1 and PROKR2 HA–tagged receptors. Both cell lines were used to characterize the receptors expression, to establish a functional assay, to determine the efficient conditions for the assay and to test the selected molecules. Among the 330 selected molecules, 15 could be tested. Only three molecules showed a specific inhibitory effect on the interaction of EG–VEGF with its receptor PROKR2. Both molecules are in the process to be tested in vitro and in vivo on animal models.
Karen now works with Dr. Florence Cammas from Institut du cancer de Montpellier.