Photocatalytic assembly of ligands for drug discovery

Project overview: Kinetic target-guided synthesis (KTGS) is a fragment-based drug discovery (FBDD) approach in which the protein of interest is able to both select good binders and promote their linking through irreversible bond formation, in a single-step process.[1] In situ click chemistry, pioneered by Sharpless and colleagues, is the most use KTGS reaction for the identification of multisite ligands. However, this strategy requires significant entropic contributions to overcome high activation barriers, which can result in a long incubation time (up to several days), when tolerated by proteins, to counterbalance its low reactivity.[2] Based on this observation, we investigated the use of a photochemical transformation as a complementary ligation approach, to accelerate KTGS reactions to an unprecedented level (Photo-KTGS).[3] This research program aims to combine photocatalysis with KTGS for the first time, to develop new reactions without background activity.

Le laboratoire CARMeN (ex COBRA), crée le 01 Janvier 1996, est une unité mixte de recherche (UMR-6064) associant l’Université de Rouen Normandie, l’INSA Rouen Normandie, le CNRS, l'Université de Caen Normandie et ENSICAEN. Le doctorat sera réalisé dans le laboratoire localisé dans le bâtiment de l’IRCOF à Mont-Saint-Aignan.
L’objectif scientifique global du laboratoire COBRA est de développer des méthodes innovantes en synthèse organique, chimie analytique et modélisation moléculaire et de les appliquer à différents sous-domaines de la discipline (chimie bioorganique, chimie pharmaceutique, chimie éco-responsable, chimie des matériaux) en s’appuyant sur une équipe de recherche en analyse performante.

We are looking for highly motivated candidates with a strong interest in working at the interface of organic chemistry and biology. This multidisciplinary project will involve organic synthesis, bioconjugation, LC-MS/MS analyses and enzymatic assays. Experience in bioconjugation or protein purification would be a plus.