
Feline coronavirus drug inhibits the main protease of SARS-CoV-2 - miked85
https://www.nature.com/articles/s41467-020-18096-2
======
JoshuaEddy
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_coro...](https://www.reddit.com/r/COVID19/comments/ihvkku/feline_coronavirus_drug_inhibits_the_main/g37b4lz/?context=3)

~~~
sradman
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)

------
aqme28
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
> 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)

~~~
aqme28
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
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.

------
devit
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...](https://chemistry-
europe.onlinelibrary.wiley.com/doi/full/10.1002/cbic.202000047)].

What's new? And also, how come this hasn't already been tested?

~~~
CJefferson
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.

------
sillysaurusx
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
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
> Is there a cure for HIV?

Yes:

[https://www.washingtonblade.com/2020/08/17/fda-approves-
huma...](https://www.washingtonblade.com/2020/08/17/fda-approves-human-trial-
for-treatment-to-cure-hiv/)

~~~
projektfu
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.

------
ShroudedNight
I remember this article about GS-441524[1] cropping up a few months ago:

[https://www.theatlantic.com/science/archive/2020/05/remdesiv...](https://www.theatlantic.com/science/archive/2020/05/remdesivir-
cats/611341/)

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
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

------
sradman
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_(pharmacolo...](https://en.wikipedia.org/wiki/Protease_inhibitor_\(pharmacology\))

------
HarryHirsch
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.

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

~~~
aqme28
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
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.

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

~~~
cowboysauce
In this context irreversibility means that once the drug binds with its
target, it's done. It can't unbind.

