SySMiC, Research Themes

In collaboration with different teams in France and abroad, our team is involved in the development of different types of inhibitors targeting different pathologies such as tuberculosis.

According to the recent World Health Organization (WHO) report, tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) affects nearly 10 million people worldwide. The emergence of drug-resistant mycobacterial strains, such as multidrug-resistant tuberculosis (MDR-TB), extensively drug-resistant tuberculosis (XDR-TB) and extensively drug-resistant tuberculosis (XDR-TB), augurs well for a growing incidence, leading to an increase in the number of victims. In the last 40 years, few anti-tuberculosis drugs, including bedaquiline, delamanide and preomanide have been approved by the US-FDA for MDR-TB, but resistance is already emerging. This is why it is necessary to identify new molecules capable of eradicating tuberculosis. The enzymes involved in the biosynthesis of mycolic acids represent privileged cellular targets for the discovery of new antituberculosis drugs, in particular proteins belonging to the fatty acid synthesis system (FASII), which is not present in humans. One of them, the enzyme InhA, essential for Mtb survival, is particularly studied in our group.

Design and synthesis of GEQ-type inhibitors against the enzyme InhA:

A PDB structure (1P45a) showed that two triclosan molecules could bind to the InhA protein binding site. From this structure, two triclosan-based macrocycles were synthesized and evaluated against InhA and mycobacterial strains. One of them called M02 showed encouraging inhibitory activity against the InhA enzyme (Bioorg. Chem. 2020, 95, 103498). Based on this result, different macrocyclic molecules will be designed. The modulation of the chemical structure of these macrocyclic inhibitors is guided by molecular modeling and is based on iterative cycles of synthesis/evaluation/optimization by docking.

Over the years, organic chemists have developed methods to synthesize macrocycles to favor the cycling event over the undesirable oligomerization event. For this purpose, the use of confined media, such as biological or other systems, may represent a relevant strategy. Indeed, cavities associated with confined systems can induce essential steric constraints through an adequate pre-organization of the acyclic precursor molecule before the promotion of the macrocyclisation process. Confinement should promote the proximity of complementary functional groups in the same molecule and facilitate the intramolecular cyclic closure reaction to create a new ligand with enhanced binding properties to the target.