Molecular mechanisms of TMPRSS2 in SARSCoV-2 infection: conformational variability of loops and targeting with small compounds

Trabajo fin de máster presentado en la Université Paris-Cité para el Master Bioinformatique - Parcours In Silico Drug Design, en junio de 2022
The outbreak and spread of SARS-CoV-2 in 2019 caused massive lockdowns, triggering a global health and global economic crisis. The initial social distance strategies and lately vaccination are controlling the pandemics for current variants, but on the long term we need more therapeutic options. Hoffman et al. showed that TMPRSS2 was essential for the infection of the respiratory tract. In fact, TMPRSS2 competes for the priming of the binding furin site, a polybasic insertion only present on the SARS-CoV-2 spike protein. However, this region has not been resolved yet. In the absence of models of the molecular complex, it is essential to characterize the molecular complex between TMPRSS2 and the spike protein, to understand the molecular mechanisms of SARS-CoV-2 and to design new drugs. In this work, we have been able to model the furin binding site of the spike protein, a loop, which was absent in all experimental structures. Then, we characterized the spike-TMPRSS2 complex. Our results showed that loop morphology is fundamental in this process, demonstrating that priming can only occur with the open conformation of the spike protein. Finally, the characterization of this complex allowed us to find protein-protein inhibitors, being Antipain, a serine protease inhibitor, our best candidate to target this complex. In conclusion, this study has demonstrated the importance of loops in protein-protein interactions and opens the door to the inhibition of other respiratory diseases, avoiding drug resistance and the impact of new genetic variants.