(5−7) To develop improved therapeutics against SARS-CoV-2, understanding the molecular mechanism of viral entry and/or hijacking the host system and its interplay with the different and host proteins is imperative. In different countries, various levels of virulence and pathogenicity have been identified, which could be due to the variance in viral strains and host factors, including host genetic makeup. (4) To date, it has infected more than 520 million people resulting in more than 6.2 million deaths with varied incidences across the globe ( as of May 2022.
SARS-CoV-2 is an enveloped, single-stranded positive-sense RNA β-coronavirus (3) belonging to the family Coronaviridae, similar to SARS-CoV-1 and MERS-CoV-2. The coronavirus disease 2019 (COVID-19) pandemic, caused by the highly transmissible and virulent pathogen severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global health emergency (1,2) causing severe acute respiratory distress syndrome (ARDS) in humans. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic. This article is made available via the ACS COVID-19 subset for unrestricted RESEARCH re-use and analyses in any form or by any means with acknowledgement of the original source. These findings reveal the role of TMPRSS2 in the activation of SARS-CoV-2 for its entry and insight into possible intervention strategies. On the basis of structure-guided drug screening, we also report the potential TMPRSS2 inhibitors and their structural interaction in blocking TMPRSS2 activity, which could impede the interaction with the spike protein. By employing computational modeling and structural analyses, we modeled the macromolecular structure of TMPRSS2 in complex with S-protein, which incited the mechanism of S-protein processing or cleavage for a new path of viral entry.
First, we identified three potential TMPRSS2 cleavage sites in the S2 domain of S-protein (S2′, T1, and T2) and reported the structure of TMPRSS2 with its individual catalytic triad.
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Here, using biochemical, structural, computational, and molecular dynamics approaches, we investigated how TMPRSS2 recognizes and activates the S-protein to facilitate viral entry. However, the structural and molecular interplay between TMPRSS2 and S-protein remains enigmatic. Recent studies have highlighted the molecular details of furin and S-protein interaction. The SARS-CoV-2 spike glycoprotein (S-protein) engages with host receptor ACE2 for adhesion and serine proteases furin and TMPRSS2 for proteolytic activation and subsequent entry. Understanding the cell entry mechanism of SARS-CoV-2 and its entire repertoire is a high priority for developing improved therapeutics. The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected more than 520 million people around the globe resulting in more than 6.2 million as of May 2022.
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