For the first time, an analysis by liquid NMR spectroscopy of the SARS-CoV-2 dimeric protease (3CLp) has been carried out, by the Lille NMR sites. This study determined that the F01 fragment is a protase inhibitor with antiviral activity in infected cells.

With the support of the 3CLPRO-SCREEN-NMR project and the infranalytics site, researchers from Lille have joined forces* to study the cysteine ​​protease 3CLpro, an essential enzyme of SARS-CoV-2 which cuts the polyproteins pp1a and pp1ab in functional units. The results obtained make it possible to understand the complex regulatory mechanisms of this enzyme, which must assemble into a dimer to allow its active site, endowed with significant plasticity, to adopt the appropriate conformation to accommodate the substrate and cut it. Based on these results, the authors performed an NMR screening of molecular fragments against the 3CLproa protease, which identified three different binding sites, two within the active site and one at the dimerization interface. . In addition, the F01 fragment from this screening was shown to be able to inhibit the enzymatic activity of the 3CLpro protease in vitro and the replication of SARS-CoV-2 in cultures of infected cells. This F01 fragment will now have to be optimized in order to increase its effectiveness. The results will provide insight into the complex interactions between active site plasticity, dimerization and 3CLpro enzymatic activity. These results are published in Angewandte Chemie International Edition.