Mechanistic insights of host cell fusion of SARS-CoV-1 and SARS-CoV-2 from atomic resolution structure and membrane dynamics

Abstract

The emerging and re-emerging viral diseases are continuous threats to the wellbeing of human life. Previous outbreaks of Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS had evidenced potential threats of coronaviruses in human health. The recent pandemic due to SARS-CoV-2 is overwhelming and has been going beyond control. Vaccines and antiviral drugs are ungently required to mitigate the pandemic. Therefore, it is important to comprehend the mechanistic details of viral infection process. The fusion between host cell and virus being the first step of infection, understanding the fusion mechanism could provide crucial information to intervene the infection process. Interestingly, all enveloped viruses contain fusion protein on their envelope that acts as fusion machine. For coronaviruses, the spike or S glycoprotein mediates successful infection through receptor binding and cell fusion. The cell fusion process requires merging of virus and host cell membranes, and that is essentially performed by the S2 domain of the S glycoprotein. In this review, we have discussed cell fusion mechanism of SARS-CoV-1 from available atomic resolution structures and membrane binding of fusion peptides. We have further discussed about the cell fusion of SARS-CoV-2 in the context of present pandemic situation.

Enhanced Cholesterol-Dependent Hemifusion by Internal Fusion Peptide 1 of SARS Coronavirus-2 Compared to Its N-Terminal Counterpart

“…The fusion domain of SARS-CoV spike protein (S2) contains three putative fusion peptides recognized as the N-terminal fusion peptide (FP), internal fusion peptide 1 (IFP1), and internal fusion peptide 2 (IFP2). 9 − 13 The S2 protein contains heptad repeats, HR1 and HR2, and a transmembrane region at the C-terminus in addition to these fusion peptides. Interestingly, the FP and IFP1 are highly homologous between SARS-CoV-1 and SARS-CoV-2 ( Table 1 ).…”

Virus-Mediated Cell-Cell Fusion

“…SARS-CoV and SARS-CoV-2 both utilize ACE2 (Angiotensin converting enzyme 2) as host receptor to enter into lung type II epithelial target cells (also called pneumocytes) [ 115 , 116 , 117 , 125 , 126 , 132 , 139 , 140 , 141 ]. Like for MERS-CoV, priming and activation of the S protein involve serine proteases, such as TMPRSS2, for exposure of the S2 domain fusion peptide required for fusion of viral and cellular membranes, as well as for triggering cell-cell fusion between neighboring target cells [ 121 , 142 , 143 , 144 , 145 , 146 , 147 , 148 ]. In addition, the S protein of SARS-CoV-2 and MERS-CoV contains, unlike the SARS-CoV S protein, an additional multibasic cleavage site used by the cellular serine protease furin before subsequent activation by TMPRSS2, thus promoting cell-cell fusion and virus cell-to-cell spreading in lung cells [ 148 ].…”

Exploring novel and potent cell penetrating peptides in the proteome of SARS-COV-2 using bioinformatics approaches

“…For example, the upstream region of the heptad repeat1 (HR1) (residues 892–972) in S2 domain of SARS-CoV spike glycoprotein was involved in membrane fusion. Moreover, some scientists have recognized membrane binding peptides and membrane fusogenic peptides or potential fusion peptides from the upstream region of HR1 (residues 758–890) [ 35 ]. Indeed, an efficient membrane fusion mechanism between host cell and SARS-CoV-2 can be responsible for virus infection.…”