Abstract:The ongoing COVID-19 pandemic has already caused over a million deaths worldwide, and this death toll will be much higher before effective treatments and vaccines are available. The causative agent of the disease, the coronavirus SARS-CoV-2, shows important similarities with the previously emerged SARS-CoV-1, but also striking differences. First, SARS-CoV-2 possesses a significantly higher transmission rate and infectivity than SARS-CoV-1 and has infected in a few months over 60 million people. Moreover, COVID… Show more
“…Because expression of TMPRSS2 and ACE2R are regulated through the andro-corticosteroid signaling pathway [7, 11, 30], we examined the genetic sequence identity of the glucocorticoid and androgen receptors across multiple species associated with propagation of SARS-CoV-2 ( Fig 4 ). Comparing sequences of the androgen receptor ( Fig 4A ) indicated a high degree of identity between all species analyzed, with sequence concordance values with the human gene ranging from 84.62 (golden hamster) and 85.47 (greater horseshoe bat) to 98.26 (sunda pangolin).…”
Section: Resultsmentioning
confidence: 99%
“…The spike glycoprotein of SARS-CoV-2 has two domains, the S1 domain comprising residues 12 – 667 and the S2 domain, comprising residues 668-1273. The S1 subunit contains the receptor binding domain (RBD), which interacts with the ACE2 receptor, whereas the S2 subunit remains associated with the viral envelope [7]. Viral infection requires proteolytic cleavage at Arg685-Ser686 at the S1 site by the transmembrane protease, serine 2 (TMPRSS2), followed by cleavage at the S2 site at Arg815-Ser816 [6].…”
Since its initial discovery in late 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of COVID19, has spread worldwide and despite significant research efforts, treatment options remain limited. Replication of SARS-CoV-2 in lung is associated with marked infiltration of macrophages and activation of innate immune inflammatory responses triggered, in part, by heightened production of interleukin-6 (IL-6) that recruits lymphocytes to the site of infection that amplify tissue injury. Antagonists of the glucocorticoid and androgen receptors have shown promise in experimental models of COVID19 and in clinical studies, because cell surface proteins required for viral entry, angiotensin converting enzyme 2 (ACE2) and the transmembrane serine protease 2 (TMPRSS2), are transcriptionally regulated by these receptors. We therefore postulated that the glucocorticoid (GR) and androgen receptor (AR) antagonist, PT150, would reduce infectivity of SARS-CoV-2 and prevent inflammatory lung injury in the Syrian golden hamster model of COVID19. Animals were infected intranasally with 2.5 x 10e4 TCID50/ml equivalents of SARS-CoV-2 (strain 2019-nCoV/USA-WA1/ 2020) and PT150 was administered by oral gavage at 30 and 100 mg/Kg/day for a total of 7 days. Animals were then examined at days 3, 5 and 7 post-infection (DPI) for lung histopathology, viral load and production of proteins regulating the initiation and progression of SARS-CoV-2 infection. Results of these studies indicated that oral administration of PT150 decreased replication of SARS-CoV-2 in lung, as well as expression of ACE2 and TMPRSS2 protein. Hypercellularity and inflammatory cell infiltration driven by macrophage responses were dramatically decreased in PT150-treated animals, as was tissue damage and expression of IL-6. Molecular modeling suggested that PT150 binds to the co-activator interface of the ligand binding domain of both AR and GR and thereby acts as an allosteric modulator and transcriptional repressor of these receptors. Phylogenetic analysis of AR and GR across multiple species permissive to SARS-CoV-2 infection revealed a high degree of sequence identity maintained across species, including human, suggesting that the mechanism of action and therapeutic efficacy observed in Syrian hamsters would likely be predictive of positive outcomes in patients. PT150 is therefore a strong candidate for further clinical development for the treatment of COVID19 across variants of SARS-CoV-2.
“…Because expression of TMPRSS2 and ACE2R are regulated through the andro-corticosteroid signaling pathway [7, 11, 30], we examined the genetic sequence identity of the glucocorticoid and androgen receptors across multiple species associated with propagation of SARS-CoV-2 ( Fig 4 ). Comparing sequences of the androgen receptor ( Fig 4A ) indicated a high degree of identity between all species analyzed, with sequence concordance values with the human gene ranging from 84.62 (golden hamster) and 85.47 (greater horseshoe bat) to 98.26 (sunda pangolin).…”
Section: Resultsmentioning
confidence: 99%
“…The spike glycoprotein of SARS-CoV-2 has two domains, the S1 domain comprising residues 12 – 667 and the S2 domain, comprising residues 668-1273. The S1 subunit contains the receptor binding domain (RBD), which interacts with the ACE2 receptor, whereas the S2 subunit remains associated with the viral envelope [7]. Viral infection requires proteolytic cleavage at Arg685-Ser686 at the S1 site by the transmembrane protease, serine 2 (TMPRSS2), followed by cleavage at the S2 site at Arg815-Ser816 [6].…”
Since its initial discovery in late 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of COVID19, has spread worldwide and despite significant research efforts, treatment options remain limited. Replication of SARS-CoV-2 in lung is associated with marked infiltration of macrophages and activation of innate immune inflammatory responses triggered, in part, by heightened production of interleukin-6 (IL-6) that recruits lymphocytes to the site of infection that amplify tissue injury. Antagonists of the glucocorticoid and androgen receptors have shown promise in experimental models of COVID19 and in clinical studies, because cell surface proteins required for viral entry, angiotensin converting enzyme 2 (ACE2) and the transmembrane serine protease 2 (TMPRSS2), are transcriptionally regulated by these receptors. We therefore postulated that the glucocorticoid (GR) and androgen receptor (AR) antagonist, PT150, would reduce infectivity of SARS-CoV-2 and prevent inflammatory lung injury in the Syrian golden hamster model of COVID19. Animals were infected intranasally with 2.5 x 10e4 TCID50/ml equivalents of SARS-CoV-2 (strain 2019-nCoV/USA-WA1/ 2020) and PT150 was administered by oral gavage at 30 and 100 mg/Kg/day for a total of 7 days. Animals were then examined at days 3, 5 and 7 post-infection (DPI) for lung histopathology, viral load and production of proteins regulating the initiation and progression of SARS-CoV-2 infection. Results of these studies indicated that oral administration of PT150 decreased replication of SARS-CoV-2 in lung, as well as expression of ACE2 and TMPRSS2 protein. Hypercellularity and inflammatory cell infiltration driven by macrophage responses were dramatically decreased in PT150-treated animals, as was tissue damage and expression of IL-6. Molecular modeling suggested that PT150 binds to the co-activator interface of the ligand binding domain of both AR and GR and thereby acts as an allosteric modulator and transcriptional repressor of these receptors. Phylogenetic analysis of AR and GR across multiple species permissive to SARS-CoV-2 infection revealed a high degree of sequence identity maintained across species, including human, suggesting that the mechanism of action and therapeutic efficacy observed in Syrian hamsters would likely be predictive of positive outcomes in patients. PT150 is therefore a strong candidate for further clinical development for the treatment of COVID19 across variants of SARS-CoV-2.
“…This is perhaps most strikingly demonstrated by the findings from many research labs that SARS-CoV-2 rapidly adapts to growth in Vero cells via small deletions in its S1/S2 priming site, with one outcome being a reduction of virus transmission in animal models [ 64 ]. While coronaviruses have always adapted to cell culture, and there are several examples where this has occurred by selecting alternative proteases for virus entry, the rapidity of selection seen for SARS-CoV-2 is unprecedented—and also in line with certain sequences derived from non-respiratory tissues from autopsies [ 65 •• ], leading to questions about the relevance of cell or tissue-type selection of novel variants along with utilization of their cognate proteases in the context of viral pathogenesis [ 66 ]. Figure 1 A coronavirus entry triad.…”
Because of the COVID-19 pandemic, the novel coronavirus SARS-CoV-2 has risen to shape scientific research during 2020, with its spike (S) protein being a predominant focus. The S protein is likely the most complicated of all viral glycoproteins and is a key factor in immunological responses and virus pathogenesis. It is also the driving force dictating virus entry mechanisms, which are highly “plastic” for coronaviruses, allowing a plethora of options for different virus variants and strains in different cell types. Here we review coronavirus entry as a foundation for current work on SARS-CoV-2. We focus on the post-receptor binding events and cellular pathways that direct the membrane fusion events necessary for genome delivery, including S proteolytic priming and activation. We also address aspects of the entry process important for virus evolution and therapeutic development.
“…Interaction of SARS-CoV-2 with hACE2 occurs via the S protein on the viral envelope. Proteases cleave the S protein into S1 and S2 subunits 2,3,4 to enable viral binding to hACE2 5 and viral entry by membrane fusion 6 . The S protein is a homotrimer and the S1 subunit of each of the monomers of the S protein contains the receptor-binding domain (RBD; Fig.…”
The SARS-CoV-2 viral genome mutates incessantly as it spreads in the world and the gene for the Spike (S) protein, critical for viral transmission into humans, is no exception. Analysis of 4,517 variants isolated from humans identified regions with few mutations, thus pinpointing important functional and structural sites in the S protein. This information can guide the development of effective prophylactic agents to arrest the spread of the COVID-19 pandemic.
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