5 ms·

Feline coronavirus drug inhibits the main protease of SARS-CoV-2

120 points by miked85 6y ago

sradman 6y ago
The paper describes a protease inhibitor [1] that was previously developed for cats: > Feline infectious peritonitis, a fatal coronavirus infection in cats, was successfully treated previously with a prodrug GC376, a dipeptide-based protease inhibitor. GC376 and its precursor GC373 "...are potent inhibitors of SARS-CoV-2 replication in cell culture." Since these drugs are safe in cats, it gives hope for safety and efficacy in human trials. An effective treatment of SARS-CoV-2 (and other coronaviruses) complements the vaccine effort. [1] https://en.wikipedia.org/wiki/Protease_inhibitor_(pharmacology) https://en.wikipedia.org/wiki/Protease_inhibitor_(pharmacolo...
devit 6y ago
According to Wikipedia [https://en.wikipedia.org/wiki/GC376 https://en.wikipedia.org/wiki/GC376], it seems this had already been suggested months ago, as early as February 5th [https://chemistry-europe.onlinelibrary.wiley.com/doi/full/10.1002/cbic.202000047 https://chemistry-europe.onlinelibrary.wiley.com/doi/full/10...]. What's new? And also, how come this hasn't already been tested?
- CJefferson 6y ago
  What's new is testing this works on COVID-19. When you say it hasn't already been tested, this is testing? Research and peer review takes a while.
- vmchale 6y ago
  Too busy enrolling people for hydroxychloroquine trials.
- projektfu 6y ago
  They could use Remdesivir and hydroxychloroquine off-label in empirical trials because they were already approved drugs. To use these drugs on COVID patients you would need a pre-marketing study or some other special dispensation.
JoshuaEddy 6y ago
From discussion the scientific /r/Covid19 subreddit: > Flawed article (not testing in cells expressing TMPRSS2 and / or Furin), gets upvoted 800 times... the usual Reddit COVID19 story... Two months ago an article said pretty much the same. Both articles only test antiviral properties in Vero E6 cells, which is not useful, since HCQ is also very effective in Vero E6 cells, but overall underperforms. https://www.reddit.com/r/COVID19/comments/ihvkku/feline_coronavirus_drug_inhibits_the_main/g37b4lz/?context=3 https://www.reddit.com/r/COVID19/comments/ihvkku/feline_coro...
- sradman 6y ago
  Why would spike binding matter for a protease inhibitor that works within the cell? Regardless, human kidney organoids with ACE2 receptors are available [1] so the question switches to why the human kidney organoid people don't coordinate with the GC376 drug makers for fast in-vitro experiments. This is where the WHO and its member nation states should have stepped up. I'm assuming that I'm misunderstanding some fundamental aspect of the drug development process since Apeiron APN01 seemed like a promising potential treatment in April but it appears to have followed the status-quo human trial pace. [1] https://www.cell.com/cell/pdf/S0092-8674(20)30399-8.pdf https://www.cell.com/cell/pdf/S0092-8674(20)30399-8.pdf
  - deleted 6y ago
    [deleted]
  - deleted 6y ago
    [deleted]
- Izkata 6y ago
  > > since HCQ is also very effective in Vero E6 cells, but overall underperforms. ...didn't Switzerland accidentally prove hydroxychloroquine works? During the period it was banned (with a two-week lag time for the virus to run its course) the death rate among resolved cases nearly tripled (scroll down to the first graph): http://www.francesoir.fr/societe-sante/covid-19-hydroxychloroquine-works-irrefutable-proof http://www.francesoir.fr/societe-sante/covid-19-hydroxychlor...
PaulHoule 6y ago
Aren't the odds like 1-in-100 that an antiviral that works "in vitro" also works "in vivo?"
- aqme28 6y ago
  It works in vivo in cats and is already in active use, which should raise the odds of this working in vivo in humans by a lot.
  - PaulHoule 6y ago
    True, cats seem to be wracked with viruses. I've had to feed mine acyclovir. I think cats may get antivirals more than humans do.
- refurb 6y ago
  Based on typical pre-clinical to approval rates, 1 in 100 is on the optimistic side.
- Ancapistani 6y ago
  My favorite response to "in vitro" trials is that a 12ga shotgun is often 100% effective in vitro.
aqme28 6y ago
My first cat passed away from FCoV. It's an incredibly brutal and strange disease. At least according to my vet, there's no analogous pathology in humans. It's like if the common cold mutated about 5% of the time in a way that was 100% fatal.
- sradman 6y ago
  > Feline infectious corona peritonitis (FIP) is the name given to a common and aberrant immune response to infection with feline coronavirus (FCoV). [1] Sounds like it is primarily a gastro-intestinal disease. EDIT: > An experimental antiviral drug called GC376 was used in a field trial of 20 cats: 7 cats went into remission, and 13 cats responded initially but relapsed and were euthanized. This drug is not yet (as of 2017) commercially available. [2] [1] https://en.wikipedia.org/wiki/Feline_infectious_peritonitis https://en.wikipedia.org/wiki/Feline_infectious_peritonitis [2] https://journals.sagepub.com/doi/10.1177/1098612X17729626 https://journals.sagepub.com/doi/10.1177/1098612X17729626
  - dependenttypes 6y ago
    Cats seem to have a lot of issues caused by their own immune system, other one that comes to my mind is https://en.wikipedia.org/wiki/Vaccine-associated_sarcoma https://en.wikipedia.org/wiki/Vaccine-associated_sarcoma
  - aqme28 6y ago
    Gastrointestinal sure, but the cause of death is due to fluid buildup in the space around the lungs (peritoneum) which progressively prevents the lungs from expanding. Watching my cat die from that was the most horrible thing I've witnessed.
    - serf 6y ago
      I've had two cats die from FIP. Rather than breathing problems, it expressed itself as a wasting disease. (non-effusive FIP) The cats (wanted to) ate practically 24/7, their hunger being unable to be satisfied. Terrible diarrhea, leading to liver failure and death over the course of a week from first apparent symptoms. One of the cats became so jaundiced that her eyes and skin were almost a florescent yellow before her death. The other experienced such radical muscle atrophy in his hinds after just two weeks of symptoms that he became immobile. He shortly after suffered a stroke or similar such anomaly and died a few days after becoming immobile. He still had a voracious appetite -- even after becoming immobile. It's a brutal and devastating disease for felines. It's also easily transmissible between neighborhood cats. It's a horrible diagnosis to hear from a vet -- it harbors very little hope for the patient. The only silver lining is the usual quickness of the death. I'm sorry that you and your pets had to go through it.
HarryHirsch 6y ago
But does this compound do anything for patient survival? We are seeing similar things for GS-441524. It works for FIP, but remdesivir does nothing for survival in patients with COVID-19 pneumonia, perhaps because the disease is much more fulminant. It wouldn't be a stretch to think that that also holds true for 3CL protease inhibitors.
akavel 6y ago
The article mentions "reversibility" - what does it mean here? What kind of reversibility?
- cowboysauce 6y ago
  In this context irreversibility means that once the drug binds with its target, it's done. It can't unbind.
- projektfu 6y ago
  Reversible means that there is an equilibrium of E + D <-> ED where E is enzyme and D is drug, and ED is the "complex" molecule. Irreversible binding looks like: E + D --> ED where the product on the right is effectively unable to become the molecules on the left again. An example of irreversible binding is COX-2 and aspirin.
ShroudedNight 6y ago
I remember this article about GS-441524[1] cropping up a few months ago: https://www.theatlantic.com/science/archive/2020/05/remdesivir-cats/611341/ https://www.theatlantic.com/science/archive/2020/05/remdesiv... There was some weird cynicism about Remdesivir being some baroque equivalent to GS-441524 (which was supposedly buried) which, if I recall correctly, supposedly enabled extra patent shenanigans. I'm curious how these (GC373, GC376) relate. [1] A Remdesivir-related drug sold through shady channels used to treat FIP / Feline infectious peritonitis
- eggsnbacon1 6y ago
  Remdesivir is a prodrug that converts to GS-441524 in the body. https://pubs.acs.org/doi/10.1021/acsmedchemlett.0c00316 https://pubs.acs.org/doi/10.1021/acsmedchemlett.0c00316 By most anecdotal accounts GS-441524 is better and possibly safer. And its readily available on the black market for treatment of cat FIP because apparently its much easier to make than Remdesivir. So yes, probably the only reason Remdesivir exists is patents
- projektfu 6y ago
  GC373 and GC376 are protease inhibitors. They inhibit enzymes that cleave proteins, hopefully being specific to their target viruses. GS-441524 is a nucleoside analog. RNA is made up of nucleosides (actually nucleotides, which have nucleosides as building blocks). It gets incorporated during replication of the viral genome and causes termination of viral replication.
sillysaurusx 6y ago
Does anyone know why there's so little cat research? FeLV, FCoV... My two cats died from FeLV. It's a hard problem to cure it, but, is it really impossible? It just seems like there's no money being thrown at the problem. Are the incentives just not there?
- projektfu 6y ago
  Money is an issue. FeLV is vaccine-preventable, reducing the pressure to cure it. It's also a retrovirus, making cures harder to come by. Is there a cure for HIV? There appear to be working chronic treatments that make life nearly indistinguishable from being infected, but the only known cure is total immune grafting. VS-FCoV (the mutant we care about) appears unpredictably. It mutates from the more quotidian, diarrhea-causing feline CoV. Perhaps if we had known that there was a pandemic coronavirus on the horizon, people would have dumped more money into studying it than they did into "bioterrorism organisms", and maybe there would have been a cure by now. I agree, it would have been nice. It's an awful disease. Fundamentally, cures appear as a matter of luck. If you have more people studying a disease, you will probably find a cure sooner, but that is no guarantee.
  - garmaine 6y ago
    > Is there a cure for HIV? Yes: https://www.washingtonblade.com/2020/08/17/fda-approves-human-trial-for-treatment-to-cure-hiv/ https://www.washingtonblade.com/2020/08/17/fda-approves-huma...
    - projektfu 6y ago
      Maybe. Hopefully. Getting approval to run a Phase 1 does not mean we have a cure. We will have more confidence after this study finishes.

120 points by miked85 6y ago

The paper describes a protease inhibitor [1] that was previously developed for cats: > Feline infectious peritonitis, a fatal coronavirus infection in cats, was successfully treated previously with a prodrug GC376, a dipeptide-based protease inhibitor. GC376 and its precursor GC373 "...are potent inhibitors of SARS-CoV-2 replication in cell culture." Since these drugs are safe in cats, it gives hope for safety and efficacy in human trials. An effective treatment of SARS-CoV-2 (and other coronaviruses) complements the vaccine effort. [1] https://en.wikipedia.org/wiki/Protease_inhibitor_(pharmacology) https://en.wikipedia.org/wiki/Protease_inhibitor_(pharmacolo...

devit 6y ago

According to Wikipedia [https://en.wikipedia.org/wiki/GC376 https://en.wikipedia.org/wiki/GC376], it seems this had already been suggested months ago, as early as February 5th [https://chemistry-europe.onlinelibrary.wiley.com/doi/full/10.1002/cbic.202000047 https://chemistry-europe.onlinelibrary.wiley.com/doi/full/10...]. What's new? And also, how come this hasn't already been tested?

CJefferson 6y ago
What's new is testing this works on COVID-19. When you say it hasn't already been tested, this is testing? Research and peer review takes a while.
vmchale 6y ago
Too busy enrolling people for hydroxychloroquine trials.
projektfu 6y ago
They could use Remdesivir and hydroxychloroquine off-label in empirical trials because they were already approved drugs. To use these drugs on COVID patients you would need a pre-marketing study or some other special dispensation.

JoshuaEddy 6y ago

From discussion the scientific /r/Covid19 subreddit: > Flawed article (not testing in cells expressing TMPRSS2 and / or Furin), gets upvoted 800 times... the usual Reddit COVID19 story... Two months ago an article said pretty much the same. Both articles only test antiviral properties in Vero E6 cells, which is not useful, since HCQ is also very effective in Vero E6 cells, but overall underperforms. https://www.reddit.com/r/COVID19/comments/ihvkku/feline_coronavirus_drug_inhibits_the_main/g37b4lz/?context=3 https://www.reddit.com/r/COVID19/comments/ihvkku/feline_coro...

sradman 6y ago
Why would spike binding matter for a protease inhibitor that works within the cell? Regardless, human kidney organoids with ACE2 receptors are available [1] so the question switches to why the human kidney organoid people don't coordinate with the GC376 drug makers for fast in-vitro experiments. This is where the WHO and its member nation states should have stepped up. I'm assuming that I'm misunderstanding some fundamental aspect of the drug development process since Apeiron APN01 seemed like a promising potential treatment in April but it appears to have followed the status-quo human trial pace. [1] https://www.cell.com/cell/pdf/S0092-8674(20)30399-8.pdf https://www.cell.com/cell/pdf/S0092-8674(20)30399-8.pdf
- deleted 6y ago
  [deleted]
- deleted 6y ago
  [deleted]
Izkata 6y ago
> > since HCQ is also very effective in Vero E6 cells, but overall underperforms. ...didn't Switzerland accidentally prove hydroxychloroquine works? During the period it was banned (with a two-week lag time for the virus to run its course) the death rate among resolved cases nearly tripled (scroll down to the first graph): http://www.francesoir.fr/societe-sante/covid-19-hydroxychloroquine-works-irrefutable-proof http://www.francesoir.fr/societe-sante/covid-19-hydroxychlor...

PaulHoule 6y ago

Aren't the odds like 1-in-100 that an antiviral that works "in vitro" also works "in vivo?"

aqme28 6y ago
It works in vivo in cats and is already in active use, which should raise the odds of this working in vivo in humans by a lot.
- PaulHoule 6y ago
  True, cats seem to be wracked with viruses. I've had to feed mine acyclovir. I think cats may get antivirals more than humans do.
refurb 6y ago
Based on typical pre-clinical to approval rates, 1 in 100 is on the optimistic side.
Ancapistani 6y ago
My favorite response to "in vitro" trials is that a 12ga shotgun is often 100% effective in vitro.

aqme28 6y ago

My first cat passed away from FCoV. It's an incredibly brutal and strange disease. At least according to my vet, there's no analogous pathology in humans. It's like if the common cold mutated about 5% of the time in a way that was 100% fatal.

sradman 6y ago
> Feline infectious corona peritonitis (FIP) is the name given to a common and aberrant immune response to infection with feline coronavirus (FCoV). [1] Sounds like it is primarily a gastro-intestinal disease. EDIT: > An experimental antiviral drug called GC376 was used in a field trial of 20 cats: 7 cats went into remission, and 13 cats responded initially but relapsed and were euthanized. This drug is not yet (as of 2017) commercially available. [2] [1] https://en.wikipedia.org/wiki/Feline_infectious_peritonitis https://en.wikipedia.org/wiki/Feline_infectious_peritonitis [2] https://journals.sagepub.com/doi/10.1177/1098612X17729626 https://journals.sagepub.com/doi/10.1177/1098612X17729626
- dependenttypes 6y ago
  Cats seem to have a lot of issues caused by their own immune system, other one that comes to my mind is https://en.wikipedia.org/wiki/Vaccine-associated_sarcoma https://en.wikipedia.org/wiki/Vaccine-associated_sarcoma
- aqme28 6y ago
  Gastrointestinal sure, but the cause of death is due to fluid buildup in the space around the lungs (peritoneum) which progressively prevents the lungs from expanding. Watching my cat die from that was the most horrible thing I've witnessed.
  - serf 6y ago
    I've had two cats die from FIP. Rather than breathing problems, it expressed itself as a wasting disease. (non-effusive FIP) The cats (wanted to) ate practically 24/7, their hunger being unable to be satisfied. Terrible diarrhea, leading to liver failure and death over the course of a week from first apparent symptoms. One of the cats became so jaundiced that her eyes and skin were almost a florescent yellow before her death. The other experienced such radical muscle atrophy in his hinds after just two weeks of symptoms that he became immobile. He shortly after suffered a stroke or similar such anomaly and died a few days after becoming immobile. He still had a voracious appetite -- even after becoming immobile. It's a brutal and devastating disease for felines. It's also easily transmissible between neighborhood cats. It's a horrible diagnosis to hear from a vet -- it harbors very little hope for the patient. The only silver lining is the usual quickness of the death. I'm sorry that you and your pets had to go through it.

HarryHirsch 6y ago

But does this compound do anything for patient survival? We are seeing similar things for GS-441524. It works for FIP, but remdesivir does nothing for survival in patients with COVID-19 pneumonia, perhaps because the disease is much more fulminant. It wouldn't be a stretch to think that that also holds true for 3CL protease inhibitors.

akavel 6y ago

The article mentions "reversibility" - what does it mean here? What kind of reversibility?

cowboysauce 6y ago
In this context irreversibility means that once the drug binds with its target, it's done. It can't unbind.
projektfu 6y ago
Reversible means that there is an equilibrium of E + D <-> ED where E is enzyme and D is drug, and ED is the "complex" molecule. Irreversible binding looks like: E + D --> ED where the product on the right is effectively unable to become the molecules on the left again. An example of irreversible binding is COX-2 and aspirin.

ShroudedNight 6y ago

I remember this article about GS-441524[1] cropping up a few months ago: https://www.theatlantic.com/science/archive/2020/05/remdesivir-cats/611341/ https://www.theatlantic.com/science/archive/2020/05/remdesiv... There was some weird cynicism about Remdesivir being some baroque equivalent to GS-441524 (which was supposedly buried) which, if I recall correctly, supposedly enabled extra patent shenanigans. I'm curious how these (GC373, GC376) relate. [1] A Remdesivir-related drug sold through shady channels used to treat FIP / Feline infectious peritonitis

eggsnbacon1 6y ago
Remdesivir is a prodrug that converts to GS-441524 in the body. https://pubs.acs.org/doi/10.1021/acsmedchemlett.0c00316 https://pubs.acs.org/doi/10.1021/acsmedchemlett.0c00316 By most anecdotal accounts GS-441524 is better and possibly safer. And its readily available on the black market for treatment of cat FIP because apparently its much easier to make than Remdesivir. So yes, probably the only reason Remdesivir exists is patents
projektfu 6y ago
GC373 and GC376 are protease inhibitors. They inhibit enzymes that cleave proteins, hopefully being specific to their target viruses. GS-441524 is a nucleoside analog. RNA is made up of nucleosides (actually nucleotides, which have nucleosides as building blocks). It gets incorporated during replication of the viral genome and causes termination of viral replication.

sillysaurusx 6y ago

Does anyone know why there's so little cat research? FeLV, FCoV... My two cats died from FeLV. It's a hard problem to cure it, but, is it really impossible? It just seems like there's no money being thrown at the problem. Are the incentives just not there?

projektfu 6y ago
Money is an issue. FeLV is vaccine-preventable, reducing the pressure to cure it. It's also a retrovirus, making cures harder to come by. Is there a cure for HIV? There appear to be working chronic treatments that make life nearly indistinguishable from being infected, but the only known cure is total immune grafting. VS-FCoV (the mutant we care about) appears unpredictably. It mutates from the more quotidian, diarrhea-causing feline CoV. Perhaps if we had known that there was a pandemic coronavirus on the horizon, people would have dumped more money into studying it than they did into "bioterrorism organisms", and maybe there would have been a cure by now. I agree, it would have been nice. It's an awful disease. Fundamentally, cures appear as a matter of luck. If you have more people studying a disease, you will probably find a cure sooner, but that is no guarantee.
- garmaine 6y ago
  > Is there a cure for HIV? Yes: https://www.washingtonblade.com/2020/08/17/fda-approves-human-trial-for-treatment-to-cure-hiv/ https://www.washingtonblade.com/2020/08/17/fda-approves-huma...
  - projektfu 6y ago
    Maybe. Hopefully. Getting approval to run a Phase 1 does not mean we have a cure. We will have more confidence after this study finishes.