Abstract
At the time of reception of this article (April 2, 2020), efforts to develop a specific vaccine against SARS-Cov-2, the causative agent of the coronavirus disease 2019 (COVID-19), had just begun trial phase 1, but full validation of this and other current developments is likely to take many more months to reach completion. The ongoing pandemic constitutes a major health burden of world proportions that is also having a devastating impact on whole economies worldwide, the knock-on effects of which could be catastrophic especially in poorer countries. Alternative measures to ameliorate the impact and hamper or minimally slow down disease progression are urgently called for. This review discusses past and currently evolving data on the etiological agent of the current pandemic, SARS-CoV-2, and its host cell receptors with a view to disclosing alternative drugs for palliative or therapeutic approaches. Firstly, SARS-CoV-2 exhibits marked tropism for cells that harbor the membrane-bound metalloprotease angiotensin-converting enzyme 2 (ACE2) at their plasmalemma, predominantly in cells lining the oral cavity, upper respiratory tract, and bronchoalveolar cells, making these epithelial mucosae the most likely viral receptor cell targets and entry routes. Secondly, the crystal structures of several coronavirus spike proteins in complex with their cell host target receptors, and of SARS-Cov-2 in complex with an inhibitor, are now available at atomic resolution through X-ray diffraction and cryo-electron microscopy studies. Thirdly, viral entry of other viruses has been successfully blocked by inhibiting viral endogenous proteases or clathrin/dynamin-dependent endocytosis, the same internalization pathway followed by ACE2 and some viruses. Fourthly, the target cell-surface receptor molecules and SARS-CoV-2 possess other putative sites for drugs potentially modulating receptor activity or virus processing. A multi-pronged pharmacological approach attacking more than one flank of the viral-receptor interactions is worth considering as a front-line strategy.
Highlights
Human coronaviruses (HCoVs) were discovered in 1965 in patients with the common flu and coined B814, with the prefix “corona” subsequently added in reference to their relatively large spikes resembling a crown (Li, 2013)
The SARS-CoV enters human epithelial cells in vitro through the apical surface, and viruses replicated in these cells are released via the apical plasmalemma. This correlates with the cellular distribution of its main molecular target at the plasmalemma, the angiotensin-converting enzyme 2 (ACE2), which in well-differentiated epithelial cells is more abundantly expressed at the apical surface than in the basolateral membranes and is used by SARS-CoV to readily infect such differentiated cells (Jia et al, 2005)
The structure is quite similar to that of the S protein from the human beta-CoV HKU1-CoV obtained by cryoEM (Kirchdoerfer et al, 2016). Another recent cryo-electron microscopy (cryo-EM) study has resolved the structure of the full-length human ACE2 with or without the receptor binding domain (RBD) of the S1 spike protein of SARS-CoV-2, in the presence of a neutral amino acid transporter, B◦AT1, which awards stability to the crystal structure, at a resolution of 2.9 Å (3.5 Å at the RBD) (Yan et al, 2020)
Summary
Human coronaviruses (HCoVs) were discovered in 1965 in patients with the common flu and coined B814, with the prefix “corona” subsequently added in reference to their relatively large spikes (or spines) resembling a crown (Li, 2013). HCoVs in the second group are more pathogenic and share the tropism for epithelial cells containing membrane bound proteases; they are the etiological agents responsible for the severe acute respiratory syndrome (SARSCoV), Middle East respiratory syndrome (MERS-CoV), and the ongoing outbreak of CoV disease (COVID-19) purportedly originating in the city of Wuhan, Hubei province in China. The potential emergence of a SARS-like cluster of a circulating bat CoV, SHCO14-CoV, with experimentally demonstrated human cell infective capacity and high pathogenicity, was already reported in 2015 (Menachery et al, 2015). Genetic, and pathogenic aspects of CoVs reiterated the warning (Su et al, 2016): “considering the high frequency of recombination of these viruses, with unpredictable changes in virulence, and with multiple viral species hosted by different animals that are likely to interact with each other, it is not a matter of if, but of when, a new CoV will emerge and cause a new outbreak of human disease.”. Genetic, and pathogenic aspects of CoVs reiterated the warning (Su et al, 2016): “considering the high frequency of recombination of these viruses, with unpredictable changes in virulence, and with multiple viral species hosted by different animals that are likely to interact with each other, it is not a matter of if, but of when, a new CoV will emerge and cause a new outbreak of human disease.” The current, perhaps inevitable outbreak of COVID-19 attests to the correctness of these predictions
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
