The broad spectrum antiviral ivermectin targets the host nuclear transport importin α/β1 heterodimer (Australia, 2020-05)

[-] TrumpLyftAlles | 5 points | Aug 09 2020 18:48:30

This is long-held theory about ivermectin's action, presented in the original Monash 48 hours study that kicked off interest in ivermectin when it was published in early April -- that ivermectin prevents entry to the cell nucleus by binding to the importin α/β1 heterodimer. The researchers are at Monash, probably the same team.

I can't get the full paper, unfortunately.

Highlights

• The FDA-approved broad spectrum antiviral small molecule ivermectin targets host importin α/β1 heterodimer.

• Ivermectin can dissociate the host importin α/β1 heterodimer/prevent reassociation.

• Ivermectin can inhibity not only DENV, but also WNV and ZIKV, all of which are major burdens for human health.

• Ivermectin is a compelling prospect as a therapeutic for infection by flaviviruses and other pathogenic viruses.

I'm still struggling with understanding what this means for COVID-19. The authors don't address COVID-19 directly, though they DO write about several other viruses.

Glossary:

Dissociation = breaking into parts

NLS = nuclear localization signal (? search this)

α-helicity = helical character, especially of DNA, it's shape (I guess)

#Abstract Infection by RNA viruses such as human immunodeficiency virus (HIV)-1, influenza, and dengue virus (DENV) represent a major burden for human health worldwide. Although RNA viruses replicate in the infected host cell cytoplasm, the nucleus is central to key stages of the infectious cycle of HIV-1 and influenza, and an important target of DENV nonstructural protein 5 (NS5) in limiting the host antiviral response.

A brief look around didn't turn up evidence that NS5 is relevant for covid-19.

We previously identified the small molecule ivermectin as an inhibitor of HIV-1 integrase nuclear entry, subsequently showing ivermectin could inhibit DENV NS5 nuclear import, as well as limit infection by viruses such as HIV-1 and DENV. We show here that ivermectin's broad spectrum antiviral activity relates to its ability to target the host importin (IMP) α/β1 nuclear transport proteins responsible for nuclear entry of cargoes such as integrase and NS5.

We establish for the first time that ivermectin can dissociate the preformed IMPα/β1 heterodimer, as well as prevent its formation, through binding to the IMPα armadillo (ARM) repeat domain to impact IMPα thermal stability and α-helicity.

We show that ivermectin inhibits NS5-IMPα interaction in a cell context using quantitative bimolecular fluorescence complementation. Finally, we show for the first time that ivermectin can limit infection by the DENV-related West Nile virus at low (μM) concentrations. Since it is FDA approved for parasitic indications, ivermectin merits closer consideration as a broad spectrum antiviral of interest.

This study doesn't say so, but my recollection is that covid-19 enters the nucleus and thereby interferes with the cell's normal immune response.

[-] RobbyN2 | 1 points | Aug 09 2020 21:10:10

More info from Dr. Been if interested. He is a good explainer. IMHO.

https://youtu.be/rFE3XE68Wfw

[-] TrumpLyftAlles | 1 points | Aug 10 2020 03:04:37

Thanks for the link. Not much new.

He says that ivermectin is dangerous to infants because they do not have a fully-developed blood-brain barrier. This was once widely believed, but it has been established that humans develop effective blood-brain barriers in the womb.

The most important info for me was the assertion that covid-19 proteins enter the cell and disable the cell's defense mechanisms. I have been trying to find a source about that, no luck so far.

He said ivermectin needs to be taken early, like HCQ. This contradicts the ICON study that found that IVM reduced fatalities 52% among patients who were sick enough to require 02. Dr. Aguirre (Peru) has a protocol where the dose of IVM increases as the disease severity increases, including in the most severe stage. The Sermo data, surveying MDs treating covid-19, says that 60% or so of MDs find that IVM is very or extremely effective in the ICU.

There are a lot of unkowns.

I appreciate that Dr. Been is getting the word out about ivermectin. Thanks again for the link.

[-] RobbyN2 | 2 points | Aug 10 2020 11:20:35

Agreed. Many unknowns and our understanding of things rapidly changes. Stay well!

[-] pathfinder1980z | 1 points | Aug 10 2020 19:15:14

I worry about the dose recommendations here:

here is the study

[-] TrumpLyftAlles | 2 points | Aug 10 2020 19:25:04

This is the favorite attack on ivermectin, replicated in at least 10 articles. It is the IVM equivalent of 2016's EMAILS!!! It's theorectical crap that ignores a vital aspect of covid-19: humans have an immune system. Ivermectin (or any drug) doesn't have to do the job all by itself.

This part of the study is good:

Even higher doses (up to 10× higher than approved doses) were studied in a small phase I trial.7 This trial showed that ivermectin administered orally in the fasted state was well‐tolerated both after a single 120 mg dose (10× higher than approved dose) and after 60 mg three times weekly (every 72 hours). The most common adverse events were headache, nausea, dizziness, and rash. The reported incidence and type of adverse events were relatively similar between ivermectin (24%) and placebo (35%) and did not increase with dose. All dosing regimens had a mydriatic effect (the primary safety end point based on results from toxicology studies) similar to placebo. It is important to note that although this study evaluated common adverse events, the presence and incidence of rare adverse events at these high doses are unknown, given the small number of subjects studied.

There is a trial underway that is giving patients 1200mcg/kg, for 5 consecutive days. 1200mcg is 6 times the so-called "normal dose". Giving that much for 5 days in a row is 30 times normal.

Ivermectin is ridiculously safe. It's unknown, how much is too much. It might not be possible to overdose on ivermectin (mostly kidding).

[-] pathfinder1980z | 1 points | Aug 10 2020 19:30:50

Thanks. So what’s a good dose? And do we have any citations for that recommendation.

[-] TrumpLyftAlles | 1 points | Aug 10 2020 19:34:30

200mcg/kg is the dose approved by the FDA for the treatment of parasites. What's the best dose for treatment of covid-19? No one knows -- hence the trials.

Here is the protocol of a Peru MD with a ton of front-line experience. He cranks up the dose for more severly-ill patients.

[-] pathfinder1980z | 1 points | Aug 10 2020 19:43:11

Wow. I’ve seen that protocol. It’s like the MATH+ or Norfolk stuff. Do you have higher resolution picture? I can’t read that Imgur clearly.

[-] TrumpLyftAlles | 1 points | Aug 10 2020 19:57:57

It’s like the MATH+ or Norfolk stuff.

?? What is that?

Do you have higher resolution picture? I can’t read that Imgur clearly.

Sorry, I don't. Googling for it might work.

[-] pathfinder1980z | 1 points | Aug 10 2020 20:15:33

Google the MATH+ protocol. Surprised you haven’t followed that.

[-] am6502 | 1 points | Aug 10 2020 23:44:29

It is fortunate that the dose of locally applied ivermectin is for a significant amount of time many orders of magnitude higher than the dose averaged over the whole body.

[-] TrumpLyftAlles | 1 points | Aug 11 2020 00:24:41

locally applied ivermectin

Are you talking about skin cream? I imagine you could sleep for a week in a bathtub of skin cream without adverse effects. Based on nothing of course; that experiment has not yet been performed. ;)

[-] am6502 | 2 points | Aug 11 2020 00:31:05

throat lozenge or nostril application via q-tip

[-] TrumpLyftAlles | 1 points | Aug 11 2020 00:46:38

Wow! Where ARE you? I have never heard of ivermectin throat lozenges. I guess q-tip implies a liquid form of ivermectin? That's not a thing in the US AFAIK. Maybe for veterinary use; I know almost nothing about that.

[-] am6502 | 2 points | Aug 11 2020 01:11:43

in gel form.

[-] TrumpLyftAlles | 2 points | Aug 11 2020 02:12:55

I'm unaware of that, too. Thanks for the education.

[-] covid-19_throwaway | 3 points | Aug 09 2020 19:34:55

Though the paper's paywalled, author David Jans has been working on this general subject for several years now, it's mostly elaboration on earlier research.

[-] TrumpLyftAlles | 2 points | Aug 10 2020 03:11:47

Hi, covid-19_throwaway! It's been a while! How are you?

Thanks for the link. Yeah, it reads a lot like the paywalled article.

Importantly, we establish for the first time that ivermectin has potent antiviral activity towards both HIV-1 and dengue virus, both of which are strongly reliant on importin α/β nuclear import, with respect to the HIV-1 integrase and NS5 (non-structural protein 5) polymerase proteins respectively.

I spent some time today googling to see if I could find anything about importin α/β1 being relevant to COVID-19. No luck. Do you happen to know about that? A search for covid-19 AND NS5-IMPα also came up dry.

Oh, Dr. Jans is at Monash. That place was a hive of ivermectin expertise, when this virus hit. I'm grateful that their early April 48 hours study got the ball rolling. That paper is referenced constantly.

[-] covid-19_throwaway | 1 points | Aug 10 2020 04:25:29

Doing fine, thanks, for being in a pandemic.

There's a good intro in about the middle of this page: https://www.sigmaaldrich.com/technical-documents/protocols/biology/ncov-coronavirus-proteins.html

[-] thaw4188 | 2 points | Aug 09 2020 21:40:07

I figure US medical system will finally catch onto this in volume maybe December 2020/January 2021 when everything else runs out and CDC/NIH finally starts becoming unleashed from the current nightmare administration.

Still like this explainer best so far but it's going to take a large study with "omg it works" to change minds over here:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261036/figure/Fig2/

[-] TrumpLyftAlles | 1 points | Aug 10 2020 09:16:48

That's a great image, thanks!