Capitol Hill Blue Forums Science and Technology Health, Medicine & the healing Sciences Coronavirus: The Plague of The 21st Century?

As it is established that SARS-CoV-2 shares the same cellular entry receptor as SARS-CoV, the ACE2 binding efficacy of S-protein was observed to be 10–20 fold higher in SARS-CoV-2 in a recent study (Song et al., 2018). It was also observed that human cells expressing ACE2 but not human Dipeptidyl peptidase-4 (DPP4) or Aminopeptidase N (APN) were less susceptible to the human cell entry of SARS-CoV-2 (Letko et al., 2020). The priming of Spike (S) protein following the binding to the ACE2 receptor results in the viral- host cell fusion (Tortorici and Veesler, 2019). The cathepsin L-dependent viral glycoprotein activation via SARS-CoV S-protein cleavage at S1/S2 boundary under low pH conditions and involvement of transmembrane protease serine 2 (TMPRSS2) in triggering the cleavage of trimer S-protein (Simmons et al., 2005; Millet and Whittaker, 2015) opened new avenues to study the role and participation of different proteases in the endocytosis of SARS-CoV-2 into human cells as well as potential for drug targeting and vaccine development. The observed increase in binding efficiency of SARS-CoV-2 S-glycoprotein to the host receptor can be related to the codon mutations observed in the protein sequence, resulting in a plausible increase in the site-specific priming activity of proteases and cathepsins, leading to the highly contagious nature of SARS-CoV-2 as compared to SARS and MERS. Proteases belonging to the proprotein convertase family, including furin and furin-like serine proteases, were analyzed for their ubiquitous role in viral entry and spread. Although produced in the endoplasmic reticulum and role in the viral biosynthesis, these furin and furin-like proteases were found translocated through secretory pathways to access viral S-protein and promote viral entry to host cells (Seidah and Prat, 2012). A recent study presented results supporting the presence of a furin-like cleavage site in the spike protein of SARS-CoV-2, which was absent in the other beta coronaviruses (Coutard et al., 2020). It was previously presented that, compared to lower pathogenic forms of the influenza virus, highly pathogenic versions selectively possess a furin-like cleavage site, replaced by a single basic residue cleavage site present in the less pathogenic viruses (Sun et al., 2010; Kido et al., 2012). Another group of researchers correlated the presence of a furin site in the envelope protein to the elevated levels of plasminogen observed in severe COVID-19 patients (Ji et al., 2020). Further research focusing on site-specific binding studies could be an approach to reveal potential druggable targets involving different proteases and specific peptide inhibitors.