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...
https://en.wikipedia.org/wiki/Angiotensin_II_receptor_blocke...
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
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.
this thread is descended from a conversation about recent discoveries and lead considerations that are not yet perfected and very probably not completely understood.
I get the idea that its tempting to try and find a physiological sweet spot where you can evade the virus,
but virus has a number of tools that work in concert to manipulate the host physiology into a working environment and exploit molecular machinery.
this ACE2 related pathology is likely multiprong so disruption of one aspect will not be sure to reduce harm.
on the flipside blood pressure modulators can be a problem with incorrect dosage. Your doctor has a better scoop on your health status then i could have in any short time so thats where you should ask about changing dosage, and getting some idea of just how much risk you might have if your exposed to the virus.
The gist of the thesis so far:
here is what we think is known so far.
ACE2 adjusts the amount of angiotensin II [given]
and when angiotensin II docks to its receptor [AT2] this results in a signal to increase your blood pressure.
this receptor [AT2] is where losartan does its job, it inhibits binding of angiotensin II to the AT2.
what the virus seems to do is dock with and disrupt the ACE2 protien, so your ability to adjust howmuch angiotensin II is free and available is disrupted.
what does this do? there is a lot more angiotensin II encountering the AT2 receptor, this causes blood pressure to go up, this causes the lungs to generate fibres between cells, this causes lung tissue to become less than optimum at being pliable elastic and permeable to gases.
This is not a good time to have a blood pressure spike. this is probably not a good time to do anything that increases the angiotensin II signal to the AT2 receptor.
your losartan _may_ actually help you.
now keep in mind this is ongoing way out to the very edge, preliminary research so dont do something risky like screwing around with these meds when this isnt even finished science.