5 ms·
What are the implications of this?
by jfries 7y ago
What are the implications of this?
- rolph 7y agothis is the mechanism a coronavirus assembly exploits to enter a cell. the virion uses a peplomer [one of its spikes] to dock with the cell at the ACE2 receptor then wrenches it apart like cutting a door right out of its frame, then the virus inserts itself into the cell leaving its envelope and protien accessories fused with the cell membrane. -if this mechanism can be blocked it will inhibit viral entry -if it can be mimmicked a vaccine is possible here is a good place to start looking at background information: https://en.wikipedia.org/wiki/Renin%E2%80%93angiotensin_system https://en.wikipedia.org/wiki/Renin%E2%80%93angiotensin_syst... This is what is so damaging to the infected cells to begin with. it disrupts an essential signalling system.
- epmaybe 7y agoAnother interesting side effect could be other temporizing measures in the inpatient setting. My understanding from a brief skim of older research papers is that the ACE inhibitors and angiotensin receptor blockers that we use today, like lisinopril or losartan, could upregulate the expression of ACE-2 receptors. If a patient is admitted with coronavirus, discontinuing blood pressure medications such as lisinopril and losartan could be worthwhile to decrease length of stay, morbidity, and mortality.
- chroem- 7y agoI suppose that explains why a lot (most?) of the people who died also suffered from high blood pressure.
- epmaybe 7y agoNo, I think that's just the fact that most of the people who died were older with lots of comorbidities, like high blood pressure, diabetes, COPD, etc
- rolph 7y agoit doesnt explain it, but it is something worth chasing to its end for a possible therapeutic benefit. its does suggest that such comorbidities such as high blood pressure or existing lung disorder disease or other wellness impairment --- --- could contribute to mortality
- rolph 7y agothis is something of a bush to beat around. - when the virus docks with the ACE2 receptor there is a loss of the ACE2 receptor function as it is a destructive process. - when the virus inhabits the cell there is probably a cytoplasmic down regulation of ACE2 expression as the cell is now "claimed" as a place for replication so the question would be when would we administer or withdraw such an ACE2 blocker the loss of ACE2 functionality is devastating to the cell but the presence of functional ACE2 receptor makes a cell vulnerable to entry -and should we be using a blocker pe se or should we use some sort of hypothetical receptor inhibitor that is not displace by coronavirus spike protien, as in competetive inhibition?
- ptest1 7y agoI wrote a long comment and it got deleted, argh! Best guess? ACE2 loss is probably bad, having more ACE2 probably doesn’t drive disease severity: https://twitter.com/__philipn__/status/1229568317167243264?s=21 https://twitter.com/__philipn__/status/1229568317167243264?s... Relative ace2 reduction correlates w disease severity; viral load growth the same between groups - check out study! Chinese paper discusses this as well: https://pubmed.ncbi.nlm.nih.gov/32061198-inhibitors-of-ras-might-be-a-good-choice-for-the-therapy-of-covid-19-pneumonia/?from_single_result=Inhibitors+of+RAS+covid https://pubmed.ncbi.nlm.nih.gov/32061198-inhibitors-of-ras-m... They reason that 1) ARB doesn’t increase ACE2 past normal human baseline anyway, just to normal status 2) Younger have higher ACE2, older women more than older men; both groups more protected so disease severity unlikely from higher ACE2. ACE2-fc being developed- will both stop AT1R activation and neutralize virus: https://twitter.com/robertlkruse/status/1233986542097567744?s=21 https://twitter.com/robertlkruse/status/1233986542097567744?... He is looking for funding if any funders are reading this. Comment here and I can connect.
- rolph 7y agothere would be an upper concentration of ACE2 receptor per unit of cell membrane that would elicit increased probability of receptor and viral peplomer interaction. once that concentration is reached, further increase of the docking probability would not occur. there is a dynamic here as the virus, in sufficient titre encounters the receptor, binds enters the cell and typically disrupts normal translatory events in the cytoplasm. the effect is to exclude further infection of the cell with increased copy number of virions, thus replication occurs instead of immediate cell apoptosis
- pezo1919 7y agoCan you please give me a pointer on these researches? Also its not clear to me: do blood pressure mediacations in general upregulate the expression of ACE-2, or is it possible that they downregulate it? (Not lisonopril or losartan)
- rolph 7y agoyou can do both depending on the med and there are different mechanisms of action. Also : any sort of EXPERIMENTATION should be done in a clinical setting with qualified professionals, this discussion is about scientific research and is not even close to being acceptable for clinical trials. blood pressure medication is normally prescribed with physician monitoring the patient for desirable or undesirable effect
- unsrsly 7y agoLisinopril and losartan are usually stopped in patients admitted to the hospital for an infection.
- pezo1919 7y agoSorry I don't know much about the topic. How can I find out if I have too high (?) ACE2, and what can I do about it? Are there sympthoms at least?
- rolph 7y agolook here: https://news.ycombinator.com/item?id=22458302 https://news.ycombinator.com/item?id=22458302
- caycep 7y agothe meds modulating ACE family of proteins are also commonly available as blood pressure meds, actually. But interestingly, the side effect is...coughing... But the research behind what is needed to modulate ACE is already there..
- pezo1919 7y agoSorry I don't know much about the topic. 0. How can I find out if I have too high (?) ACE2, and what can I do about it? Are there symthoms at least? 1. What does modulating ACE means? 2. Do you mean shall everyone get those blood pressure meds? Or what is the relation now with these meds in terms of action? Does it mean people who need it must get it for sure? 3. Research what is needed to modulate ACE: can you please give a pointer.
- pezo1919 7y agoDoes modulation mean increasing or decreasing ACE2? I assume it decreases and its good, right?