Jupiter wrote: "I do not see the justification for the statement "Apabetalone was shown to disrupt this interaction" in the article. This would seem to be a result of some follow-up work done in one of labs testing the anti-viral properties of the candidate drugs. Did I miss something?"
No, you didn't miss anything. I am confused by this as well. The BioRxiv paper indicates that the viral envelope protein (E) binds to BRD2 and BRD4 and "potentially disrupting BRD-histone binding by mimicking histone structure." It is unclear which of the two bromodomains, BD1 or BD2, is involved in this E interaction with BRD2/BRD4. E binding to BRD2 and/or BRD4 is suggested to interfere with the normal binding of BRD2 and/or BRD4 to the acetylated histone residues (an interaction important for control of gene transcription) and therefore E binding is hypothesized to induce "changes in host's protein expression that are beneficial to the virus." Recall that apabetalone (RVX-208), as well as other BET inhibitors, bind to the BET protein bromodomain to prevent binding to acetylated histone residues as well. This is where I get confused. If both E and apabetalone interfere with BET protein binding to acetylated histone residues, then what is the hypothesized mechanism for how apabetalone amerliorates the viral infection process? Is it the change in host gene expression? If so, how does one reconcile that both apabetalone and E binding would be predicted to modulate host gene expression? Is it specifically the binding of E to BRD2 and/or BRD4, which apabetalone may compete with and prevent?
Jupiter also wrote yesterday: "Thanks to you and rndtBL for that explanation. Interestingly, RVX is suggesting that downregulation of the ACE-2 enzyme (i.e. lessening its amount) may be beneficial (less protein for the virus to use to gain access to the cell) whereas this author is suggesting that more ACE-2 enzyme may be beneficial"
Great point. As you pointed out, Derek Lowe's article on Angiotensin and the Coronavirus highlighted some important unknowns. It is suggested that ACE2 is a cell surface protein by which SARS-CoV-2 recognizes and binds to gain cell entry. So from this perspective, reducing the cell surface abundance of ACE2 might interfere with viral entry into the cell. This may be what Resverlogix was referring to in their news release yesterday; apabetalone has been previously shown to reduce expression of ACE2. However, the only manuscript (after a quick search) that I could find was this one and it was only a modest decrease (30%, -1.3-fold) and it was observed in human whole blood treated ex-vivo for 24 hours. I would feel more confident in this proposed mechanism with some additional confirmatory data showing reduced ACE2 mRNA, total protein and cell surface protein expression in other experiments and model systems.
BDAZ
