TrumpLyftAlles | 8 points | Jul 09 2020 18:13:28

Inhibition of human adenovirus replication by the importin α/β1 nuclear import inhibitor ivermectin (US/Canada 2020-07-09)

https://jvi.asm.org/content/early/2020/07/02/JVI.00710-20

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[-] TrumpLyftAlles | 3 points | Jul 09 2020 18:21:39

The date is a guess based on the fact that I google for the last 24 hours and this study didn't turn up until today. The links to the PDF didn't yield anything.

The study is not COVID-19 specific. However, ivermectin's binding to Imp-α/β1 is a "known" explanation of why ivermectin is effective against the virus.

TL;DR: There are several mechanisms that explain ivermectin's mode of action as an inhibitor of cellular Imp-α/β1 mediated nuclear import.

I misunderstood; the interaction between the two IMP factors Imp-α and Imp-β1 is unchanged. ivermection blocks them without changing how they interact with each other.

ABSTRACT Human adenoviruses (HAdV) are ubiquitous within the human population and comprise a significant burden of respiratory illnesses worldwide. Pediatric and immunocompromised individuals are at particular risk for developing severe disease, however, no approved antiviral therapies specific to HAdV exist.

Ivermectin is an FDA-approved broad spectrum antiparasitic drug that also exhibits antiviral properties against a diverse range of viruses. Its proposed function is inhibiting the classical protein nuclear import pathway mediated by importin-α (Imp-α) and -β1 (Imp-β1). Many viruses, including HAdV, rely on this host pathway for transport of viral proteins across the nuclear envelope.

In this study we show that ivermectin inhibits HAdV-C5 early gene transcription, early and late protein expression, genome replication, and production of infectious viral progeny. Similarly, ivermectin inhibits genome replication of HAdV-B3, a clinically important pathogen responsible for numerous recent outbreaks. Mechanistically, we show that ivermectin disrupts binding of the viral E1A protein to Imp-α without affecting the interaction between Imp-α and Imp-β1. Our results further extend ivermectin's broad antiviral activity and provide a mechanistic underpinning for its mode of action as an inhibitor of cellular Imp-α/β1 mediated nuclear import.

IMPORTANCE

Human adenoviruses (HAdVs) represent a ubiquitous and clinically important pathogen without an effective antiviral treatment. HAdV infections typically cause mild symptoms, however individuals such as children, those with underlying conditions, and those with compromised immune systems can develop severe disseminated disease. Our results demonstrate that ivermectin, an FDA approved antiparasitic agent, is effective at inhibiting replication of several HAdV types in vitro. This is in agreement with the growing body of literature suggesting ivermectin has broad antiviral activity. This study expands our mechanistic knowledge of ivermectin by showing that ivermectin targets the ability of Imp-α to recognize nuclear localization sequences, without effecting the Imp-α/β1 interaction. These data also exemplify the applicability of targeting host factors upon which viruses rely as a viable antiviral strategy.

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[-] TrumpLyftAlles | 3 points | Jul 09 2020 18:42:21

I emailed this to one of the authors.

Hi, Dr. X,

I'm writing to ask if you would please send me a copy of your paper. The PDF links on this page aren't yielding anything.

Why? I have assigned myself the interesting task of collecting all things ivermectin vs COVID-19 on this reddit sub:

https://www.reddit.com/r/ivermectin/  

I (and others) have assembled over 300 studies, articles and news stories over the last three months.

Your study isn't directly about COVID-19, but there seems to be consensus that ivermectin's binding to Imp-α/β1 is how it prevents entry to the cell nucleus, where (I believe?) the virus ordinarily does things that disable the cell's defense mechanisms. If you want to explain that better, please do!

If you want to explain your study's relevance to COVID-19, that would be great.

From your study:

Mechanistically, we show that ivermectin disrupts binding of the viral E1A protein to Imp-α without affecting the interaction between Imp-α and Imp-β1.

Does that mean ivermectin leaves Imp-β1 intact so it remains a way for the virus to enter the nucleus?    Thanks for your work, and if you are so inclined, thanks for your explanation(s), the PDF of your study!

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[-] TrumpLyftAlles | 2 points | Jul 09 2020 22:22:03

I got the preprint from the author! Now I need to try to read it.

Unfortunately he didn't explain anything.

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[-] stereomatch | 1 points | Jul 13 2020 09:04:24

Did they mention dosing ?

We have the Australian Monash study the complaint that IC50 levels require 35x more dosing of ivermectin than typically given for deworming etc.

Yet at reasonable dosing Ivermectin is effective against a range of viral diseases.

So how does that work ?

Is the IC50 the only indicator - or could ivermectin be having other mechanisms, or may impact normally exponential viral growth in initial stages in ways that are not quantifiable in an in vitro (test tube) study ?

The preliminary data on Ivermectin for covid19 (Bangladesh, Peru, Chile) seem to suggest visible impact.

Regarding dosing being at 35x lower levels, I wonder if these factors are leveling the disparity.

Ivermectin spec sheets say bioavailability is 2.5x if you take it with a fatty meal - the mexican/spanish video posted recently mentioned taking ivermectin with fatty meal - milk, oil or avocado:

https://www.reddit.com/r/ivermectin/comments/hpstzl/_/ Video promoting Ivermectin use

In addition the Peru etc are giving 2x the daily 200mcg/kg dose - and giving it for 2 days (2x more).

For the ones who still have symptoms after 2 days, they are repeating the dosing (2x more).

This means for these studies, they are using:

2 x 2 x 2 x 2.5 = 20x

ie 20x the 200mcg/kg dose.

Which means they already getting close to the 35x dose needed for IC50.

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