This blog post says the ivermectin action identified in Monash 48 hours is "not possible" because covid19 doesn't replicate in the nucleus.
I won't replicate entirety of the article, in part because of its illustration. It has a link to a /r/covid19 conversation!
The mechanism of action of ivermectin in parasitic infections is thought to be inhibition of anion flux through a glutamate-controlled chloride channel present in the parasites, killing them by neurotoxicity. But the channel is not found in humans. Nor in viruses. Mechanisms, however, can always be conjured up. Here’s one from the same thread of comments:
[Quoted from the /r/covid19 thread]
Importin (IMP) α/β1 is a heterodimer that binds to the SARS-CoV-2 cargo protein and moves it into the nucleus which reduces the host cell antiviral response. Ivermectin destabilizes the Impα/β1 heterodimer, prevents it from viral protein binding and thus from entering the nucleus.
This, perhaps convincing sounding mechanism, based on some in vitro evidence in other viruses, has been dusted off, with apparent authority, to explain the action of ivermectin in covid-19. But we have no evidence that this proposed mechanism is at all relevant (Figure 2). In fact, it can’t be relevant, because (spoiler alert) SARS-CoV-2 doesn’t enter the nucleus to replicate; it replicates in the cytoplasm.
TIL for me, that the virus doesn't replicate in the nucleus.
If ivermectin is at all effective, an action on an importin of any kind isn’t the mechanism. Most of the time when we choose a drug to test, we seem to be entering a dark covid-19 tunnel. Is ivermectin the light at the end of the tunnel, or is it, as so often seems to be the case, just the light of a train coming in the other direction?
As ever, we are reduced to mouthing the same old trite truism, that we must wait for the results of well designed trials, preferably double-masked and placebo-controlled.
An absence of replication in the nucleus does not preclude a virus from entering and disabling the nucleus.
Thank-you!
That was my recollection, that covid19 disables the cell's defense mechanisms by doing bad things in the nucleus. I tried to find a source for that, failed: cellular biology papers are really tough for me to understand!
Is it known, where covid19 replicates? I couldn't find that either.
Yes it is known where SARS-COV-2 replicates. It is a RNA virus. Most RNA viruses replicate in the cytoplasm, and most DNA viruses replicate in the nucleus (there are exceptions for both). I'm not aware of any particular papers regarding this, but I have no reason to question it.
I can see the argument that an RNA virus is less likely to affect a nucleus, but I cannot see why an RNA virus can't also disrupt the nucleus. That poster would need to post a source for me to believe RNA viruses not only do not replicate in the nucleus, they also don't affect the nucleus in any way.
(I'm also not a cellular biologist. I'm just a layman raising my BS flag where I see it.)
[-] TrumpLyftAlles | 1 points | Jul 21 2020 17:59:13
This blog post says the ivermectin action identified in Monash 48 hours is "not possible" because covid19 doesn't replicate in the nucleus.
I won't replicate entirety of the article, in part because of its illustration. It has a link to a /r/covid19 conversation!
The mechanism of action of ivermectin in parasitic infections is thought to be inhibition of anion flux through a glutamate-controlled chloride channel present in the parasites, killing them by neurotoxicity. But the channel is not found in humans. Nor in viruses. Mechanisms, however, can always be conjured up. Here’s one from the same thread of comments:
[Quoted from the /r/covid19 thread]
Importin (IMP) α/β1 is a heterodimer that binds to the SARS-CoV-2 cargo protein and moves it into the nucleus which reduces the host cell antiviral response. Ivermectin destabilizes the Impα/β1 heterodimer, prevents it from viral protein binding and thus from entering the nucleus.
This, perhaps convincing sounding mechanism, based on some in vitro evidence in other viruses, has been dusted off, with apparent authority, to explain the action of ivermectin in covid-19. But we have no evidence that this proposed mechanism is at all relevant (Figure 2). In fact, it can’t be relevant, because (spoiler alert) SARS-CoV-2 doesn’t enter the nucleus to replicate; it replicates in the cytoplasm.
TIL for me, that the virus doesn't replicate in the nucleus.
If ivermectin is at all effective, an action on an importin of any kind isn’t the mechanism. Most of the time when we choose a drug to test, we seem to be entering a dark covid-19 tunnel. Is ivermectin the light at the end of the tunnel, or is it, as so often seems to be the case, just the light of a train coming in the other direction?
As ever, we are reduced to mouthing the same old trite truism, that we must wait for the results of well designed trials, preferably double-masked and placebo-controlled.
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[-] DZinni | 1 points | Jul 21 2020 18:38:23
Author fell for a logical fallacy.
Paraphrasing:
SARS-COV-2 doesn't replicate in the nucleus, therefore it doesn't enter the nucleus.
An absence of replication in the nucleus does not preclude a virus from entering and disabling the nucleus.
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[-] TrumpLyftAlles | 1 points | Jul 21 2020 18:42:04
An absence of replication in the nucleus does not preclude a virus from entering and disabling the nucleus.
Thank-you!
That was my recollection, that covid19 disables the cell's defense mechanisms by doing bad things in the nucleus. I tried to find a source for that, failed: cellular biology papers are really tough for me to understand!
Is it known, where covid19 replicates? I couldn't find that either.
permalink
[-] DZinni | 4 points | Jul 21 2020 19:19:53
Yes it is known where SARS-COV-2 replicates. It is a RNA virus. Most RNA viruses replicate in the cytoplasm, and most DNA viruses replicate in the nucleus (there are exceptions for both). I'm not aware of any particular papers regarding this, but I have no reason to question it.
I can see the argument that an RNA virus is less likely to affect a nucleus, but I cannot see why an RNA virus can't also disrupt the nucleus. That poster would need to post a source for me to believe RNA viruses not only do not replicate in the nucleus, they also don't affect the nucleus in any way.
(I'm also not a cellular biologist. I'm just a layman raising my BS flag where I see it.)
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[-] TrumpLyftAlles | 1 points | Jul 21 2020 19:36:42
Thanks very much for the clarification.
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