BREAKING! French Study Reveals That SARS-CoV-2 Proteins E And ORF 3a Are Not Viroporins As Previously Claimed But Are Inducers Of Pannexin Currents!
: A new study is once again causing a buzz in the scientific community as French scientist from L’institut du Thorax, Nantes Université, CNRS, INSERM, Labex Ion Channels, Science and Therapeutics, Equipe Labellisée Ligue Contre le Cancer and Institut Pasteur, Université Paris Cité have found that the SARS-CoV-2 E and ORF 3a proteins are not plasma membrane viporins (i.e. ion channels) as claimed previously but rather are inducers of pannexin currents! The study findings has enormous implications especially upon various therapeutics that were developed or under development with the fallacy that these ORF3a and E proteins were viroporins!
Expression of E or 3a protein is accompanied by altered cellular morphology but no modification in whole-cell currents in adhering cells. (A) Average current densities (±sem) recorded during the ramp protocol (inset) in adhering CHO cells expressing either only eGFP (pIRES), SARS-CoV-2 E and eGFP proteins (pIRES–E), or SARS-CoV-2 3a and eGFP proteins (pIRES–3a). (B) Superimposed brightfield and eGFP fluorescence images of CHO cells in the same 3 conditions as shown in A. (C) Morphology analysis, cf. Supplementary Figure S1. Plot of individual cells (pIRES, n = 1922; pIRES–E, n = 1198; and pIRES–3a, n = 1283), median ± interquartile range. ****: p < 0.0001 as compared to pIRES control, Kruskal-Wallis test.
Viroporins, ion channels encoded by viral genomes, have been considered potential targets for antiviral agents. Previous studies suggested that the SARS-CoV E and 3a proteins acted as plasma membrane viroporins. However, the French study aimed to better understand the cellular responses induced by these proteins, leading to astonishing findings.
The study team conducted experiments using CHO cells expressing the SARS-CoV-2 E or ORF 3a proteins. They observed that the expression of these proteins caused cell death, indicated by cell detachment and a round cell shape. Flow cytometry experiments confirmed this observation, establishing a link between the expression of E or 3a proteins and cell death.
Surprisingly, adhering cells expressing these proteins did not show significant changes in whole-cell currents compared to control cells, suggesting that E and 3a proteins are not plasma membrane viroporins. However, detached cells with altered morphology exhibited significantly larger outwardly rectifying currents.
The study team found that these currents were likely conducted by pannexin channels, which were activated by the morphological changes and potentially cell death induced by E and 3a proteins. Inhibitors of pannexin channels effectively blocked these currents. The researchers also found that inhibitors of pannexin channels, such as carbenoxolone and probenecid, were able to block these currents.
For those of you who might not know, Pannexin (Panx) channels are transmembrane proteins that facilitate intercellular communication via the release of ions and small molecules, such as adenosine triphosphate (ATP), which diffuse and bind to surface receptors on nearby cells.
The study's results challenge the viroporin hypothesis surrounding the SARS-CoV-2 E and 3a proteins and raise concerns about their cl
assification. The morphological alterations and cell death induced by these proteins may activate endogenous pannexin conductances rather than being directly linked to viroporin activity.
These study findings have significant implications for the development of therapeutics targeting SARS-CoV-2. The assumption that E and 3a proteins are viroporins has shaped previous therapeutic strategies, but this discovery challenges that notion. Understanding the role of pannexin channels in COVID-19 pathophysiology and treatment may open new avenues for developing effective treatments.
It should be noted that an earlier U.S. NIH study covered in our COVID-19 News
reports also found that ORF3a proteins were not viroporins but the study did not explore the E proteins.
The concept of viroporins as potential targets for antiviral agents has gained attention due claims of the success of drugs like amantadine, which inhibits the acid-activated M2 channel of Influenza A virus, to treat COVID-19. But with these study findings, questions will arise about the validity of previous claims about effectiveness of amantadine and other certain repurposed drugs and new biomolecules to treat COVID-19 based on the viroporin hypothesis.
Further investigations are required to fully understand the function of the E and 3a proteins in the context of COVID-19. The subcellular localization of these proteins complicates definitive testing of their intrinsic potential for channel activity. However, the study provides important insights into the link between morphological alterations, cell death, and pannexin channel activation, offering potential for new therapeutic approaches.
This groundbreaking French study serves as a reminder of the complexities involved in deciphering the functions of viral proteins. It highlights the necessity for rigorous scientific research to unravel the intricate mechanisms underlying viral infections. Developing innovative and effective treatments for COVID-19 requires a comprehensive understanding of the intricate interactions between viral proteins and host cells.
The study findings were published in the peer reviewed journal: Cells.
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