Molecular interplay between SARS‐CoV‐2 and human proteins for viral activation and entry, potential drugs for combat and scope for new therapeutics

Abstract

The pandemic Coronavirus Disease 2019 (COVID19) caused by SARS‐CoV‐2 is a serious public health concern with global morbidity over 85 million. Whilst the vaccine trials is underway, there a several antiviral and antibody treatments being clinically evaluated to fill the “therapeutic gap” in parallel. The development of potential drugs requires an understanding of SARS‐CoV‐2 pathogenicity and mechanism of action. Thus, it is essential to understand the full repertoire of viral proteins and their interplay with host factors. Here, we show how the SARS‐CoV‐2 spike protein undergoes 3 stages of processing to allow virion activation and host cell infection. Our comprehensive structural and computational studies reveal why COVID19 is hypervirulent and incites the possible reason for the failure of several antibody treatments. In addition, our resolved complex structures of spike protein with different host cell receptors shows the complexity of entry. We also demonstrate via experimental, biophysical and molecular dynamics studies that how the host proteins CD26 (DPP4), Furin and TMPRSS2 process the viral spike glycoprotein and assist in the viral entry in addition to ACE2. These results cognise the detailed mechanism of spike glycoprotein for its entry or cascade into host cell and also reveal new avenues for potential therapeutics to block different stages of viral entry and new pathways for vaccine development.