Human TMPRSS2 non-catalytic ectodomain and SARS-CoV-2 S2' subunit interaction mediated SARS-CoV-2 endocytosis: a model proposal with virtual screening for potential drug molecules to inhibit this interaction

Abstract

This study proposes a novel model for SARS-CoV-2 viral integration into the host cell via endocytosis pathway and hence a target for preventive treatment of COVID-19 infection. SARS-CoV-2 spike protein undergoes proteolytic cleavage at S1-S2 cleavage site and the cleaved out S2 domain is further cleaved by the activated serine protease domain of humanTMPRSS2 to become S2'. The activated serine protease domain of TMPRSS2 is formed after it undergoes autocatalysis by which the catalytic domain is cleaved from the membrane bound non-catalytic ectodomain (hNECD) comprising of LDLRA CLASS-I repeat and a SRCR domain. It is known that the SRCR domains as well as LDLRA repeat harboring proteins mediate endocytosis of viruses and certain ligands. Based on this, we put forward a hypothesis that the exposed hNECD binds to the S2' as both are at an interaction proximity soon after S2' is processed by the serine protease domain and this interaction may lead to the endocytosis of virus as an alternate mechanism to the direct fusion model. Based on this hypothesis we have modelled the hNECD structure, followed by protein-protein docking studies with the known 3D structure of S2'. The interaction interface of hNECD discerned from the modelled complex structure was used for virtual screening of known FDA-approved drug molecules and also some of the Indian medicinal plant-based compounds. We also mapped the known mutations of concern and mutations of interest on interaction interface of S2' and found that none of the known mutations map onto the interaction interface. This indicates that targeting the probable interaction between the hNECD of TMPRSS2 and S2' may serve as an attractive potential therapeutic target which is variant independent.