Antiviral compound blocks SARS-CoV-2 from entering cells

https://medicine.wustl.edu/news/antiviral-compound-blocks-sars-cov-2-from-entering-cells/

by WaitWaitWha • 5 years ago

186 140 5 years ago

medicine.wustl.edu

ashtonkem5• 5 years ago

I wonder if they actually used human lung cells for this test; the article doesn’t seem to specify. Past tests have used Vero cells, which are apparently the norm for virology research, but aren’t a good analogue for human cells for Covid infection. This seems to be why some compounds worked well in a Petri dish, but didn’t work in actual humans.

raphlinus4• 5 years ago

Here's the actual paper: https://www.pnas.org/content/118/43/e2108728118

There's a lot of detailed discussion about different types of cells. Vero cells don't have TMPRSS2, but Calu-3 (human lung epithelial) cells do. To dramatically oversimplify, this compound works on the latter type but not the former.

They also did a little safety testing in a mouse model. This is early stage, as you point out there are a lot of things that work well in the lab and not so much in real humans, but still I find it promising.

ashtonkem5• 5 years ago

I’m not the best reader of scientific papers, but it looks like they used human lung cells and Vero cells. I’m not qualified to speak to the rest of the experimental design, but it looks like they’ve at least avoided that old mistake.

We analyzed pseudotype entry driven by the spike protein of SARS-CoV-2 (SARS-2-S) or the glycoprotein of vesicular stomatitis virus (VSV-G) into the TMPRSS2-positive human lung cell line Calu-3 (7, 29). VSV-G was used as a control, as it does not depend on TMPRSS2 for host cell entry. Besides Calu-3 cells, we further used Vero cells (African green monkey, kidney) as a control, as these cells do not express TMPRSS2, and therefore any reduction in SARS-2-Sdriven entry would be related to either unspecific side effects or cytotoxicity.

raphlinus4• 5 years ago

I'm starting to get pretty optimistic. There seem to be a bunch of antivirals with very different mechanisms of action - this one blocks entry of the virus to cells, Molnupiravir fucks up accurate replication of the virus (nucleoside analog), others are protease inhibitors, which are very effective against HIV.

There's a caveat, most treatments that look promising don't pan out, but there are a lot in the pipeline and it seems likely that some will. What I think will happen is a cocktail of antivirals, and together these will significantly reduce the mortality. We need that, because it looks like the virus will probably be circulating endemically. The other great thing about a cocktail (as opposed to a single antiviral) is that the virus developing resistance is both less likely and less of a problem if it does happen.

ashtonkem5• 5 years ago

mRNA vaccines look extremely promising too. It’s entirely possible that some classes of cancer will be effectively eliminated in our lifetime because of it, along with HIV and/or Malaria. The latter would probably be the biggest reduction in human death and misery since the invention of the Polio vaccine

tombert3• 5 years ago

I've been saying for roughly a year now that if nothing else good can come from Covid, we at the very least are dumping a ton of time and resources and research into mRNA vaccines.

I know basically nothing about virology, but I remember hearing a podcast a million years ago talking about mRNA vaccines, and I remember after it was over thinking "if this is even half as cool as it sounds to a lay person, the implications of this are huge". It appears that it's substantially more than half as cool as it sounded, and the fact that we are even having discussions about being able to wipe out malaria is mind-boggling to me (in a good way).

mschuster91• 5 years ago

I wonder if the final stage will rather be direct production and injection of tailored antibodies instead of going around the corner by having ordinary cells express proteins that then trigger the immune system.

raphlinus4• 5 years ago

A really excellent survey on the prospects for mRNA technology from Derek Lowe: https://www.science.org/content/blog-post/what-mrna-good-and...

gizmo686• 5 years ago

A limiting factor for the effectiveness of anti-virals for Covid is time. Maximum viral load happens often happens before any symptoms are present, and the most severe diseases occurs weeks after infection as a result of the bodies inflammatory response instead of the virus itself. This means that by the time you know that a patient will have severe Covid-19, it is likely too late for any treatment that is based on interfering with the virus itself.

Having said that, we have a good demographic understanding of who tends to get severe Covid-19, and a large testing capacity, so a cheap anti-viral treatment with few side effects could still be effectively deployed.

wongarsu2• 5 years ago

I imagine the willingness to get tested would also be a lot higher if the result of a positive test was a reasonably quick antiviral treatment instead of weeks of quarantine.

Sure, there will always be sceptics, but for large parts of people, organisations and governments having less perverse incentives might improve things a lot.

beakerbreaker2• 5 years ago

That's a good point on the limitation, and to expand on your last point, an immediate demographic this could help is frontline healthcare workers and similar jobs who do get routine testing and are at higher risk in general.

UncleOxidant3• 5 years ago

Given that time is of the essence with antivirals, we need to give people lateral flow antigen tests they can take at home (very accurate if they come up positive) as well as some kind of pre-presciption (show the pharmacist your positive test result and get the antivirals or some such). Waiting for a doctors appointment will take too much time.

russdill• 5 years ago

And I'm going to hazard a guess that the likelihood of not getting early testing correlates strongly with the likelihood of not getting vaccinated.

pfdietz• 5 years ago

If the antivirals are highly effective one could really slam the immune system to stop any damaging response without the virus again going out of control.

tiahura• 5 years ago

According to the founders of Ridgeback, Molnupiravir is being tested prophylacticly. They suggested that hopefully by sometime next year, if someone you’ve been in within close contact tests positive, you get on the cocktail of Molnupiravir + the upcoming Pfizer antiviral.

tim333• 5 years ago

Molnupiravir seems pretty good. I think in the trials eight people died in the placebo group, zero with the drug.

angelzen3• 5 years ago

Molnupiravir [interferes with] accurate replication of the virus

At first glance this sound like a really bad idea, given that the #1 concern is future covid mutations.

ralusek5• 5 years ago

It specifically causes non-viable mutations. Therefore, the concern isn't currently that it'll cause mutations in the virus and create new strains, but rather that we have to be very confident that it isn't resulting in mutagenicity in mammalian cells.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8136050/

thehappypm2• 5 years ago

It's almost like we're emerging into a world just like the world when antibiotics were invented, but for antivirals. We basically had just a small handful of treatments for viruses, now there's a huge pipeline all of a sudden. Maybe in the future, having effective antivirals for just about any virus will be the norm, not the exception.

lamontcg• 5 years ago

Mortality is going to be dramatically reduced once nearly everyone has T-cells+B-cells that recognize the virus. If everyone got vaccinated we'd be out of the pandemic phase and into the endemic phase with a virus that looked more like just a flu/cold.

Vaccines are a 10x or 20x improvement in death and hospitalization rates. That's just a fact. All these antivirals won't have that kind of impact and are closing the barn doors after the horse has escaped. Which is not to say we don't research both, but vaccination is the simple easy and effective answer. There's a considerable technological fetish with antivirals while boring vaccines are now treated with skepticism, which is backwards. Antivirals should be used after vaccines have failed in vulnerable populations, the major weapon against viruses is vaccines, and they work.

penagwin• 5 years ago

PNAS October 26, 2021 118 (43) e2108728118; https://doi.org/10.1073/pnas.2108728118

I'm curious how was this published October 26, 2021? (Currently Oct 15)

vidanay• 5 years ago

Probably the date of the print publication.

beakerbreaker2• 5 years ago

That's the real advance! :)

PNAS recently moved to a continuous publication process so the paper comes out in the planned issue whenever ready rather than effectively coming out twice: once ahead-of-print and once in the issue.

https://www.pnas.org/page/updates#pnas-continuous-publicatio...

nekt2• 5 years ago

This blocks TMPRSS2 which is the exact protein ivermectin blocks.

space_fountain11• 5 years ago

Some quick googling doesn’t back this up and my understanding is that ivermectin has only shown itself to be effective at doses that are higher then are remotely safe. It also just isn’t the sort of thing there would be incentive to lie about. Probably then the straightforward story is true no it’s only effective as prescribed as treatment for parasites. If you’d like to provide some sources though or more explanation that would be great.

Note that TMPRSS2 has been a potential target for treating covid basically since the beginning, so some one lying and claiming it as a mechanism of action isn’t surprising

analyte123• 5 years ago

As far as I can tell ivermectin has only been "studied" against TMPRSS2 in silico. The better-studied purported mechanism of ivermectin against SARS-CoV-2 involves something called importin [1]. On the other hand, bromhexine, which is a cough medicine used OTC around the world does inhibit TMPRSS2 and may have action against SARS-Cov-2 [2]. Bromhexine is a prodrug for ambroxol, which is also an OTC cold medicine in much of the world.

[1] https://pubmed.ncbi.nlm.nih.gov/32251768/ [2] https://pubmed.ncbi.nlm.nih.gov/32983936/

newbamboo• 5 years ago

From the featured article “Janetka co-founded a biotechnology startup company called ProteXase Therapeutics”

I guess you could see what their business plan is?

thehappypm2• 5 years ago

"some quick googling"? Do better than this.

ralusek5• 5 years ago

I have no opinion whatsoever regarding whether or not ivermectin's purported mechanism of action against COVID is valid.

However, this:

It also just isn’t the sort of thing there would be incentive to lie about

is not true.

There are two incentives to lie about this, if you are in any way associated with drug or vaccine manufacturers.

1.) Ivermectin is out of patent and dirt cheap; basically not profitable at all

2.) Emergency use authorization for the vaccines relied on there being no available alternative treatment

Again, I have no opinion regarding whether or not ivermectin is remotely useful for COVID. But there are plenty of incentives aimed against any older generic being repurposed.

randomopining2• 5 years ago

Ivermectin doesn't have any legit studies with large samples to show that it's even that useful against covid.

Also, what happened to hydroxychloroquine? That was the big thing in 2020. guess 2021 is ivermectin.

nekt2• 5 years ago

I am not making any claims of any of these substances effectiveness in treating covid. I'm just pointing out that this substance claims to block the same human protein ivermectin does. We can all make of that what we will.

LMYahooTFY2• 5 years ago

Based on what metric?

The vaccines were authorized under emergency use with trial participants comparable to samples conducted with Ivermectin.

How is it not worth considering for a drug that's already known to be safe to administer and cheap?

Beyond that, there are practicing doctors advocating that they've had good results. This should be more than enough to consider it's use, and not dismiss it as some 'thing of the year to dismiss'.

dukeofdoom3• 5 years ago

I was reading that the flue shot also works against covid according to a study. The world will learn to live with covid. I'm more worried about the authoritarians taking advantage of the current crisis.

loonster6• 5 years ago

I remember reading in 2020 that those that have received a TB vaccine had better results with Covid. I never did find out if there was a co confounding variable that explains it. (I wouldn't be surprised if it does.)

elevenoh• 5 years ago

Inconvenient to vaccine mandates & pharma lobbyists, so will we see it prescribed?

tinus_hn2• 5 years ago

It is patented so who knows! Now instead of having to compete on producing cheap generic medicine, pharma can ask the proper question: how much are you willing to pay to be saved!

vfclists• 5 years ago

I can't believe it's not Ivermectin

Antiviral compound blocks SARS-CoV-2 from entering cells

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