Abstract
The interaction between the membrane spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the transmembrane angiotensin-converting enzyme 2 (ACE2) receptor of the human epithelial host cell is the first step of infection, which has a critical role for viral pathogenesis of the current coronavirus disease-2019 (COVID-19) pandemic. Following the binding between S1 subunit and ACE2 receptor, different serine proteases, including TMPRSS2 and furin, trigger and participate in the fusion of the viral envelope with the host cell membrane. On the basis of the high virulence and pathogenicity of SARS-CoV-2, other receptors have been found involved for viral binding and invasiveness of host cells. This review comprehensively discusses the mechanisms underlying the binding of SARS-CoV2 to ACE2 and putative alternative receptors, and the role of potential co-receptors and proteases in the early stages of SARS-CoV-2 infection. Given the short therapeutic time window within which to act to avoid the devastating evolution of the disease, we focused on potential therapeutic treatments—selected mainly among repurposing drugs—able to counteract the invasive front of proteases and mild inflammatory conditions, in order to prevent severe infection. Using existing approved drugs has the advantage of rapidly proceeding to clinical trials, low cost and, consequently, immediate and worldwide availability.
Highlights
Over the last two decades, there have been three deadly human outbreaks of coronaviruses (CoV), severe acute respiratory syndrome-CoV (SARS-CoV), Middle East Respiratory Syndrome-CoV (MERS-CoV), and SARS-CoV-2
We review some questions regarding the first stage of virus–host interaction: What are the mechanisms by which cells are infected, and what existing or potential drugs can interfere with them? We explore the early molecular processes of SARS-CoV-2 infection by highlighting the new therapeutic insights that have emerged from the various basic and clinical research studies currently underway
It has been demonstrated that the co-expression of NRP1 with angiotensin-converting enzyme 2 (ACE2) and TMPRSS2 markedly enhances the infection of SARSCoV2 [104]
Summary
Over the last two decades, there have been three deadly human outbreaks of coronaviruses (CoV), severe acute respiratory syndrome-CoV (SARS-CoV), Middle East Respiratory Syndrome-CoV (MERS-CoV), and SARS-CoV-2 The latter is causing the current pandemic called CoV disease 2019 (COVID-19). Recent studies have identified several key amino-acidic residues for S-protein interactions with the human ACE2 receptor and the TMPRSS2 membrane protease to initiate infection [6]. Given the complexity of interactions between viral proteins and host receptors with differing binding specificity and affinity, the differential prognosis for COVID-19 in SARSCoV-2 positive patients may depend on the presence of single-nucleotide polymorphism in ACE2, serine proteases, mediators or co-receptors, either individually or combined with each other or even in combination with SARS-CoV-2 genetic variants resulting in more or less virulent and lethal strains [9]. We discuss the possibility of using off-label drugs, which may have benefit of limiting the progressive spread of SARS-CoV-2 in infected individuals
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