Bioinspired scaffolds to fight human coronaviruses – CoroNat2

The COVID-19 pandemic caused by SARS-CoV-2 has highlighted the urgent need to identify antiviral compounds against human coronaviruses (HCoV). The multidisciplinary CoroNat2 project involves 4 complementary teams, each with pre-existing technical expertise in virology, phytochemistry, chemistry and proteomic. Preliminary work has identified two natural compounds isolated from plants and one synthetic analogue, all active against the coronaviruses SARS-CoV-2, SARS-CoV, MERS-CoV and HCoV-229E. The main objective is to elucidate the mechanism of action of these three molecules with common structural features and pan-coronavirus activity. Preliminary results suggest that these compounds target the replication step of SARS-CoV-2. Attention will therefore first be focused on identifying their biological targets using a multidisciplinary approach (resistant viruses, identification of mutations, differential proteomic and/or transcriptomic profiling, activity-based protein profiling, synthesis of chemoproteomic tools, ABPP (Activity-Based Protein Profiling) approach and implementation on infected cells and proteomic analysis). Concomitantly, the stability of these three molecules in solution and in cellular medium will be evaluated. After assessing their pharmacokinetic properties in a mouse model, the 3 drug candidates will be tested in two preclinical models (human primary airway epithelial cells and humanized hACE2 mice) infected with SARS-CoV-2. If the compounds are found to be active in vivo, their toxicity will be assessed in mice. Our goal is clearly to unravel the mechanism of action of new drug candidates targeting coronavirus replication, to gain fundamental knowledge of the replication step of HcoVs, and to propose new treatments against HCoVs.