Abstract
This study proposes a novel model for integration of SARS-CoV-2 into host cell via endocytosis as a possible alternative to the prevailing direct fusion model. It is known that the SARS-CoV-2 spike protein undergoes proteolytic cleavage at S1-S2 cleavage site and the cleaved S2 domain is primed by the activated serine protease domain (SPD) of humanTMPRSS2 to become S2'. The activated SPD of TMPRSS2 is formed after it is cleaved by autocatalysis 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 SPD and this interaction may lead to the endocytosis of virus. Based on this hypothesis we have modelled the hNECD structure, followed by docking studies with the known 3D structure of S2'. The interaction interface of hNECD with S2’ was further used for virtual screening of FDA-approved drug molecules and 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 interaction between the hNECD of TMPRSS2 and S2’ may serve as an attractive therapeutic target.
Communicated by Ramaswamy H. Sarma
Acknowledgments
GVK is a recipient of a Junior research fellowship and Senior research fellowship from the Council of Scientific and Industrial Research, New Delhi. GVK also acknowledges the Centre for DNA Fingerprinting and Diagnostics Core fund for supporting this work. HAN acknowledges the university core funding as well as a grant from the Department of Science and Technology, New Delhi. The authors acknowledge the Bioinformatics Infrastructure Facility (BIF), School of Life Sciences, University of Hyderabad. The authors gratefully acknowledge the engaging discussions with Prof. Dayananda and the laboratory members Dr. Chhaya Singh, Mrs. Nithya, Ms. Aishwarya Gholse, and Ms. Rachana.
Disclosure statement
The authors declare no competing interests.
Funding
The author(s) reported there is no funding associated with the work featured in this article.