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Angiotensin converting enzyme 2 (ACE2) crucial in SARS-coronavirus lung injury (2005)

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Re: Angiotensin converting enzyme 2 (ACE2) crucial in SARS-coronavirus lung injury (2005)

#41

Post by rolph »

ptest1 wrote: post #37
rolph wrote: post #10

Earlier quoted context omitted.

this 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…

I 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... 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-r…

there 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

Re: Angiotensin converting enzyme 2 (ACE2) crucial in SARS-coronavirus lung injury (2005)

#42

Post by koheripbal »

caycep wrote: post #7
jfries wrote: post #3

What are the implications of this?

the 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..

Anecdotal, but as someone who takes Losartan daily, it does not make me cough at all...

It did make my prostate feel swollen for a couple days though.

Re: Angiotensin converting enzyme 2 (ACE2) crucial in SARS-coronavirus lung injury (2005)

#43

Post by koheripbal »

CapriciousCptl wrote: post #26

__ This is not medical advice. Do not go out and take a bunch of losartan without a doctor, you could die. __ Here's the article's main point (from 2005): Kuba et al showed that by injecting losartan into mice (a common ACE inhibitor that is off patent) with a SARS-Coronavirus protein leads to less lung injury than the controls without losartan. No studies have shown this works in living, breathing humans, but... (Or…

I'm confused. Losartan is a Angiotensin II receptor blocker (ARB). I thought that was different from an ACE inhibitor...

https://en.wikipedia.org/wiki/Angiotensin_II_receptor_blocke...

Re: Angiotensin converting enzyme 2 (ACE2) crucial in SARS-coronavirus lung injury (2005)

#44

Post by rolph »

koheripbal wrote: post #43
CapriciousCptl wrote: post #26

__ This is not medical advice. Do not go out and take a bunch of losartan without a doctor, you could die. __ Here's the article's main point (from 2005): Kuba et al showed that by injecting losartan into mice (a common ACE inhibitor that is off patent) with a SARS-Coronavirus protein leads to less lung injury than the controls without losartan. No studies have shown this works in living, breathing humans, but... (Or…

I'm confused. Losartan is a Angiotensin II receptor blocker (ARB). I thought that was different from an ACE inhibitor... https://en.wikipedia.org/wiki/Angiotensin_II_receptor_blocke...

they would both have the effect of altering the state of the renin-angiotensin system

they work from different ends:

the receptor blocker, inhibits angiotensin II from binding

the ACE inhibitor, interferes with conversion of angiotensin I > angiotensin II ,,,,thus reducing the interaction between angiotensinII and the receptor.

In the case of ACE inhibitor the receptor is open and available for docking,,,in the case of the blocker, there is something that _may_ get in the way of viral peplomer docking to the receptor

ideally there exists, some sort of receptor blocker that competetively inhibits coronavirus peplomer binding but is also displaced by angiotensin II ,,, or binds in a site that does not interfere with the ligand recognition sites but prevents the binding of peplomer

Re: Angiotensin converting enzyme 2 (ACE2) crucial in SARS-coronavirus lung injury (2005)

#45

Post by ptest1 »

rolph wrote: post #44
koheripbal wrote: post #43

Earlier quoted context omitted.

I'm confused. Losartan is a Angiotensin II receptor blocker (ARB). I thought that was different from an ACE inhibitor... https://en.wikipedia.org/wiki/Angiotensin_II_receptor_blocke...

they would both have the effect of altering the state of the renin-angiotensin system they work from different ends: the receptor blocker, inhibits angiotensin II from binding the ACE inhibitor, interferes with conversion of angiotensin I > angiotensin II ,,,,thus reducing the interaction between angiotensinII and the receptor. In the case of ACE inhibitor the receptor is open and available for docking,,,in the case…

Just a little clarification. These renin-angiotensin terms are totally confusing (due to how similar they all are!) and from my correspondence with physicians, many of them even get them mixed up!

Virus binds to and downregulates ACE2. ACE2 converts Ang II to Ang 1-7. Ang II binds to AT1R and AT2R receptors:

https://twitter.com/__philipn__/status/1229607854232850432?s...

Pic for clarity.

When there’s less ACE2, and in general due to immune response, there will be more Ang II to bind to AT1R. This AT1R binding may create the lung injury seen with the virus.

The idea is that by blocking AT1R with an ARB type drug you don’t stop the virus from entering a cell, but you instead stop the body’s pathological response to the virus. After all, most viruses don’t kill us, and our immune system - if it doesn’t over react - will usually kill a thing if it has enough time and the virus isn’t “special” like HIV or herpes (that’s my general, non expert understanding!)

While it seems smart to try and inhibit ACE2 directly, there are a couple problems with this I see:

1. It may be pathological. More Ang II to bind to AT1R, you might end up way worse off. ACE2 is the “good” ACE, and all the evidence we have seems to suggest that a reduction in the ACE2:ACE ratio will make tissue fibrosis, death, etc worse. This happens in the heart and lungs in mouse models.

2. Small molecule ACE2 inhibitors bind to the C shaped area of the ACE2 enzyme, while the virus attaches to the back. So they likely may not inhibit cell entry:

https://twitter.com/robertlkruse/status/1230577662751641601?...

The best silver bullet bet here is ACE2-fc, which isn’t a small molecule.

This is a soluble form of the ACE2 protein along with an fc. this gives it a longer half life in the body.

This would likely:

1. Stop virus cell entry by neutralizing the virus- virus binds to ACE2-fc instead of the cell ACE2.

2. Stop potential lung damage from AT1R activation.

Both 1 and 2 have been shown in some models.

It is now being tested in vitro. Next animals.

Chinese are testing non-fc form, ACE2 directly, but requires IV drip. Testing now directly in humans! 7 day trial.

See twitter for more on this:

https://twitter.com/__philipn__

If you’re a funder, VC and you’re reading this: The scientist at John Hopkins who’s developing ACE2-fc is looking for funding. He’s working with Chinese biotech firms now to do the testing. Please comment here and I will connect you.

Re: Angiotensin converting enzyme 2 (ACE2) crucial in SARS-coronavirus lung injury (2005)

#46

Post by ptest1 »

rolph wrote: post #41
ptest1 wrote: post #37

Earlier quoted context omitted.

I 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... 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-r…

there 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 t…

I guess what I think could be possible is:

ARBs upregulate ACE2 but within normal physiological limit (see other comment). My understanding is it is the Ang II activation of AT2R that drives the increase in ACE2 expression. In this case, we would expect children and women (estrogen upregulates AT2R, downregulates AT1R) to have higher ACE2 in the presence of increased Ang II. I think children may have more AT2R. https://twitter.com/__philipn__/status/1233569567512772609?s... but this may be beside the point.

Other coronaviruses that use more common receptors are not as lethal. Even if the virus has a higher probability of cell entry, does that make it more lethal?

Check out this paper:

https://twitter.com/__philipn__/status/1229568317167243264?s...

Proportion of reduction of ACE2 correlates with disease severity.

Check out figure 1

“Differences in clinical outcomes did not correlate with differences in viral replication efficiencies.”

Compare C and D. Viral replication basically the same between young and old mice. But old had severe disease.

So I’m not sure it’s as simple as increased replication (a proxy for cell entry?) that drives severity.

Edit: just re read your final sentence. Great point. But in the case of ARB usage, while ACE2 may be upregulated and the cell may have another ACE2 cleaved by the virus, if AT1R blockade was occurring then maybe the lung damage would not happen.

Is the cell itself worse off with more than one copy of the virus inside of it? Or would the damage be the increased loss of ACE2?

If damage from increased loss, then I can see the ARB approach helping.

If more than one copy of virus in cell is really bad, then sounds like this could be more complicated. But I do wonder about other viruses which have lots of receptors available, and why this one is so serious in some, but not most, people.

Re: Angiotensin converting enzyme 2 (ACE2) crucial in SARS-coronavirus lung injury (2005)

#47

Post by rolph »

ptest1 wrote: post #46
rolph wrote: post #41

Earlier quoted context omitted.

there 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 t…

I guess what I think could be possible is: ARBs upregulate ACE2 but within normal physiological limit (see other comment). My understanding is it is the Ang II activation of AT2R that drives the increase in ACE2 expression. In this case, we would expect children and women (estrogen upregulates AT2R, downregulates AT1R) to have higher ACE2 in the presence of increased Ang II. I think children may have more AT2R. https…

the physiological cascade that occurs due to disruption of a homeostatic feedback system is the most probable cause of direct lethality. The setpoint and the relative concentrations of the elements in these systems are genetically dictated functions.

There is probably some correlate between predisposition to morbidity/mortality and how far ones setpoints deviate from population setpoints.

there are 2 prongs to this attack, one is the disruption of angiotensin based signalling and effectation

the other is the viral entry to the cell. the virus must do a dance on the head of a pin in a sense to replicate but not hijack somuch of the cells basic metabolism that apoptosis occurs. a virus that allows its host cell to remain viable wins the lottery for natural selection.

the problem is that the virus occupies the expression machinery that creates ACE2, in an indiscriminant fashion many other protiens as well.

so this means the virus has caused damage by entry

the entry damage causes errent feedback which causes further physiological perturberance

a secondary round of disruption occurs when ACE2 expression is inhibited thus interfereing with replenishment of ACE2 that has been damaged as well as disrupting the regular recycling of ACE2 and for that matter disrupts expression of the ATI and ATII receptors

---I am not a founder or funder but simply a concerned professional

Re: Angiotensin converting enzyme 2 (ACE2) crucial in SARS-coronavirus lung injury (2005)

#48

Post by pezo1919 »

rolph wrote: post #18
pezo1919 wrote: post #13

Earlier quoted context omitted.

Sorry 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 pleas…

have a look here ; https://news.ycombinator.com/item?id=22458302

Thanks a lot

Re: Angiotensin converting enzyme 2 (ACE2) crucial in SARS-coronavirus lung injury (2005)

#49

Post by pezo1919 »

rolph wrote: post #17
pezo1919 wrote: post #15

Earlier quoted context omitted.

Does modulation mean increasing or decreasing ACE2? I assume it decreases and its good, right?

modulation means in this case means dynamically increase or decrease in order to stay on a curve

Thanks

Re: Angiotensin converting enzyme 2 (ACE2) crucial in SARS-coronavirus lung injury (2005)

#50

Post by dnautics »

rolph wrote: post #29
dnautics wrote: post #25

Earlier quoted context omitted.

> is too new it's on bioarxiv, what exactly does 'too new' mean?

a preliminary submission has not passed a peer review with the rigor of scientific defense. these sorts of things may be passed among researchers for extended periods of time [years] until all the kinks are worked out of the thesis and a working theory with no known exceptions and independently confirmed agreement of results occurs. jan 26 2020 is the submission date.

What exactly is the standard of peer review you're expecting? Unless you have reason to think they flat out fabricated the data, the analysis is probably no better or worse than your garden variety nature or science or cell paper.
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