SARS?CoV?2 infection begins with the binding of viral S (spi...

created [InstanceEdit:9707766] Jassal, Bijay, 2020-11-20
dbId 9707813
displayName SARS?CoV?2 infection begins with the binding of viral S (spi...
modified [InstanceEdit:9770356] Stephan, Ralf, 2022-04-04
schemaClass Summation
text SARS?CoV?2 infection begins with the binding of viral S (spike) protein to the host's cell surface angiotensin converting enzyme 2 (ACE2), depending on the presence of heparan sulfate proteoglycans (HSPGs), and endocytosis of the bound virion. Inhibiting this interaction might be useful in treating patients with COVID-19. A genetically modified soluble form of ACE2, called hrsACE2 (alunacedase alfa), may decrease cell entry of SARS-CoV-2 competing for membrane-bound ACE2, therby minimizing lung injury and multiple organ dysfunction (Zoufaly et al. 2020, El-Aziz et al. 2020). In vitro studies shows that hrsACE2 reduces viral growth of SARS-CoV-2 by a factor of 1000?5000 in cell-culture, engineered human blood vessels and kidney organoids (Monteil et al. 2020). High affinity miniprotein inhibitors LCB1 and LCB3 have been shown to interact with the receptor binding domain (RBD) of the SARS-CoV-2 spike protein and block SARS-CoV-2 infection of Vero E6 cells (Cao et al. 2020). These novel inhibitors are suggested to act as viral traps and inactivators of the spike protein.

In November 2020 the FDA granted an emergency use authorization (EUA) to bamlanivimab/etesevimab, a combination of two IgG1 monoclonal antibodies directed against the spike protein of SARS-CoV-2. In a trial they showed a statistically significant reduction in viral load at day 11 (Gottlieb et al, 2021). Both were isolated from convalescent patients (Shi et al, 2020; Jones et al, 2021).

Inhibition of Spike binding to the heparan sulfate moieties of HSPGs prevents SARS-CoV-2 cell entry via ACE2, possibly by several mechanisms (Partridge et al, 2021; Paiardi et al, 2022). Heparin is an approved and widely used anticoagulant. Unfractioned heparin binds to the S1/S2 site of Spike and has a 150-fold higher antiviral effect against SARS-CoV-2 in vitro than low-molecular-weight heparin (LMWH) (Clausen et al, 2020; Kim et al, 2020; Mycroft-West et al, 2020; Liu et al, 2021; Tree et al, 2021). Several clinical studies with nebulised unfractionated heparin (UFH) are ongoing (NCT04545541, NCT04723563, NCT04635241).
Mitoxantrone is an approved neoplastic agent; it binds cell surface heparan sulfate and strongly inhibited SARS-CoV-2 cell entry with an IC50?more than?100-fold lower than that of cytotoxicity (Zhang et al, 2020). Spike protein stability depends on disulfide bonds which can be destabilized by thiol/disulfide?reactive compounds. N?acetylcysteine, L?ascorbic acid, and JTT?705 efficiently inhibited binding of S to ACE2 in vitro and inhibited pseudoviral infection in mice (Man?ek?Keber et al, 2021). Although a few clinical trials tested NAC and ascorbic acid no final assessments are available.
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