Naveen Vankadari

Conference 2022 Live Talk

 

Talk title

Structural mechanism of SARS-CoV-2 entry and activation of spike glycoprotein by engaging unique host factors and potential antiviral interventions

 

Authors and Affiliations

Naveen Vankadari1

1. Department of Biochemistry and Monash Biomedicine Discovery Institute, Monash University, Victoria 3800, Australia

 

Abstract

Background

The pandemic COVID19 disease by SARS-CoV-2 causing pneumonia and lower respiratory tract infection, is a serious public health concern with alarming mutations causing over 4.5 million deaths worldwide. Whilst effective vaccination is being administered globally, we are facing challenges with different variants, and several antiviral treatments are being clinically evaluated to fill the “therapeutic gap” to treat infected patients. The development of potential drugs or vaccines requires a thorough understanding entire repertoire of host factors involved in SARS-CoV-2 spike protein processing, entry, and pathogenicity.

Methods

We used a combination of structural, functional, molecular, and computational methods to show how the SARS-CoV-2 spike protein interacts and processed using diverse host factors. Whole exome sequencing was performed on infected and non-infected COVID19 patients to uncover the genetic variants involved in disease progression. Binding interactions were performed using the purified viral spike protein and host factors. Furthermore, molecular docking and simulations were used to decipher the real-time dynamics of viral interaction for viral entry.

Results

Our multidisciplinary research with structures studies demonstrates how SARS-CoV-2 spike protein is processed or primed in stages using human, Furin, TMPRSS2, and NRP1 for entry, in addition to ACE2, to hijack host cell entry. These insights reason for COVID19 hypervirulence and extend the possible reason for the failure of several antibody treatments and ACE2 blockers. Our exome sequencing results show that the V160M mutation in TMPRSS2 reduces disease severity in COVID19 patients. And sequencing results of 40,000 patients infer the mutations in Furin active site showed reduced COVID19 symptoms. Our structural and computational studies were helpful in the screening of potential drugs to inhibit viral infection at different stages of viral entry and targeting different host-factors.

Conclusions

These findings cognize our understanding of SARS-CoV-2 spike glycoprotein processing and the mechanism of engaging diverse host factors for cascading host-cell entry and hijacking host defence and opens the avenue for new interventions and vaccines.