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Rapid repurposing of existing drugs for COVID-19

JacksinPA

JacksinPA

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Rapid repurposing of drugs for COVID-19 | Science

Successful viral entry requires proteolytic processing of the viral coat spike glycoprotein (S), which can be carried out by TMPRSS2 (transmembrane protease serine 2) (7). The TMPRSS2 inhibitor camostat (7) is approved in Japan for the treatment of chronic pancreatitis and postoperative gastric reflux and is generally well tolerated, although rare serious side effects have been reported. Both camostat and the related agent nafamostat (8) block SARS-CoV-2 replication in TMPRSS2-expressing human cells. Camostat has been shown to block infection with SARS-CoV-2 in a mouse model. Therefore, there is a strong rationale to support clinical trials with these drugs for COVID-19, which have already been initiated in the Netherlands and Germany.
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In non-technical language, an existing drug (camostat - structure below) that is already approved for use in Japan for other conditions blocks infection of mammalian cells by COVID-19. Clinical trials in the Netherlands & Germany are already underway. We need anti-viral drugs like this one that are readily available to supplement the promised vaccine.
Camostat mesylate.jpg
 
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Every capable country is looking for solutions. My bet is on these brilliant minds to come up with treatments, cures, vaccines. Until then, and even after,we need to be cautious. Who knows what comes next.
 
JMaximus said:
Hell, with drugs like this, we may not even need a vaccine.
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Exactly. This one is already 'off the shelf' available. I don't know why Trump & Fauci haven't mentioned it because, as you can see, it's already being discussed in the open scientific literature. It's a relatively simple molecule so that it wouldn't be all that expensive.

While I have been championing inhibitors of the 2 protease enzymes generated by the virus AFTER it gets inside you, a lot of damage gets already done by then, like turning off your immune system. This one doesn't even let the virus get into your cells.
 
Lovebug said:
Every capable country is looking for solutions. My bet is on these brilliant minds to come up with treatments, cures, vaccines. Until then, and even after,we need to be cautious. Who knows what comes next.
Click to expand...

With vaccines there are go guarantees as to a) whether they will work or not, b) whether they will make you sick, and c) how long the supposed immunity will last. This drug has more short-term promise. Besides, it's a pill, not an injection.
 
Potential drug to block coronavirus identified - Neuroscience News

Potential drug to block coronavirus identified

Summary: A clinically proven drug known to block an enzyme essential for the viral entry of Coronavirus into the lungs blocks the COVID 19 (SARS-CoV-2) infection. The drug, Camostat mesilate, is a drug approved in Japan to treat pancreatic inflammation. Results suggest this drug may also protect against COVID 19. Researchers call for further clinical trials.

Source: DPZ

Viruses must enter cells of the human body to cause disease. For this, they attach to suitable cells and inject their genetic information into these cells. Infection biologists from the German Primate Center – Leibniz Institute for Primate Research in Göttingen, together with colleagues at Charité – Universitätsmedizin Berlin, have investigated how the novel coronavirus SARS-CoV-2 penetrates cells. They have identified a cellular enzyme that is essential for viral entry into lung cells: the protease TMPRSS2. A clinically proven drug known to be active against TMPRSS2 was found to block SARS-CoV-2 infection and might constitute a novel treatment option.

The findings have been published in Cell.
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This article was published in early March of this year.
 
SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor - ScienceDirect

SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option.
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This article is from April.

Here is info on the key enzyme blocked by camostat: TMPRSS2 - Wikipedia
 
SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor - PubMed

Cell
. 2020 Apr 16;181(2):271-280.e8. doi: 10.1016/j.cell.2020.02.052. Epub 2020 Mar 5.
SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor
Markus Hoffmann 1, Hannah Kleine-Weber 2, Simon Schroeder 3, Nadine Krüger 4, Tanja Herrler 5, Sandra Erichsen 6, Tobias S Schiergens 7, Georg Herrler 8, Nai-Huei Wu 8, Andreas Nitsche 9, Marcel A Müller 10, Christian Drosten 3, Stefan Pöhlmann 11
Affiliations expand
PMID: 32142651 PMCID: PMC7102627 DOI: 10.1016/j.cell.2020.02.052
Free PMC article
Abstract
The recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) in China and its rapid national and international spread pose a global health emergency. Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases. Unravelling which cellular factors are used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal therapeutic targets. Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option.
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Another article from early March.
 
Rapid repurposing has always been the best hope for treatment, hence the rush to hydroxychloriquine and remdesivir, but I agree that this development is the most promising because of where it affects the infection process. Depending on the actual severity of potential side effects (that are always minimized), it even holds promise as a prophylactic. I sense a lot of reading in my immediate future.
 
JacksinPA said:
With vaccines there are go guarantees as to a) whether they will work or not, b) whether they will make you sick, and c) how long the supposed immunity will last. This drug has more short-term promise. Besides, it's a pill, not an injection.
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I like to see all the above. Preventing is better than curing, no?
 
If you have technical questions about science and medicine, please look at the free database ScienceDirect
for abstracts of peer reviewed technical papers. You can typically purchase the full research paper or thesis for $20 to $100.
 
paul342160 said:
If you have technical questions about science and medicine, please look at the free database ScienceDirect
for abstracts of peer reviewed technical papers. You can typically purchase the full research paper or thesis for $20 to $100.
Click to expand...

Even better is PubMed, the online abstracts from the National Library of Medicine. Search by key word.
 
JacksinPA said:
Exactly. This one is already 'off the shelf' available. I don't know why Trump & Fauci haven't mentioned it because, as you can see, it's already being discussed in the open scientific literature. It's a relatively simple molecule so that it wouldn't be all that expensive.

While I have been championing inhibitors of the 2 protease enzymes generated by the virus AFTER it gets inside you, a lot of damage gets already done by then, like turning off your immune system. This one doesn't even let the virus get into your cells.
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Why aren’t they talking about it?

Antiviral drugs generally have a dismal track record.

Look at HIV. It took 20 years to come up with a decent cocktail.

The common cold has zero therapies.

Flu has a couple, and they’re pretty ineffective.

Hep C we just figured out after decades of no cure.

Every single drug that is being studied for any disease has a compelling theory behind it.

90% fail, even more in the antiviral space.
 
Threegoofs said:
Why aren’t they talking about it?

Antiviral drugs generally have a dismal track record.

Look at HIV. It took 20 years to come up with a decent cocktail.

The common cold has zero therapies.

Flu has a couple, and they’re pretty ineffective.

Hep C we just figured out after decades of no cure.

Every single drug that is being studied for any disease has a compelling theory behind it.

90% fail, even more in the antiviral space.
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I think the rationale behind camostat is compelling. That's why it's in clinical trials in 2 countries. Taking pills to prevent infection is a better course of treatment than getting a shot with no guarantee that you will not get infected.
 
JacksinPA said:
I think the rationale behind camostat is compelling. That's why it's in clinical trials in 2 countries. Taking pills to prevent infection is a better course of treatment than getting a shot with no guarantee that you will not get infected.
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Rationales are always compelling.

That’s why one invests the time and money into Phase 2 trials.

And 90% fail.
 
"Why aren't they taking about it?" Because Fauci doesn't want another rush to take an unproven antidote, and Trump's backers haven't bought stock in the company. It's a Japanese company, but watch its stock soar. (Investors have a terrible Lemming response.)
 
NWRatCon said:
"Why aren't they taking about it?" Because Fauci doesn't want another rush to take an unproven antidote, and Trump's backers haven't bought stock in the company. It's a Japanese company, but watch its stock soar. (Investors have a terrible Lemming response.)
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Fauci has to be aware of this because it's i the open scientific literature.

Ono Pharmaceutical looks like a bargain: OPHLY (OTCMKTS) $8.89 -0.09 (-1.00%)
 
JacksinPA said:
With vaccines there are go guarantees as to a) whether they will work or not, b) whether they will make you sick, and c) how long the supposed immunity will last. This drug has more short-term promise. Besides, it's a pill, not an injection.
Click to expand...

Prophylactic use of acid reflux medicine to prevent the virus may not be without other long-term side-effects.
 
There are around 100 COVID-19 vaccines in development. Some may work, many will not. And we have no way to determine how long the immunity lasts. Like the ordinary flu shot, they have to reformulate the vaccine every year to account for different strains. The COVID-19 spike protein, which many of these experimental vaccines are targeting, is known to mutate = different strains. I have no info on whether the camostat target TMPRSS2 enzyme also mutates, but camostat & related drugs are relatively simple molecules that can be manipulated chemically to provide a family of anti-viral drugs to be effective against mutant enzymes. All of this will have to be worked out in animal & clinical trials.

One problem with the vaccine approach is that it works after the virus has entered the cell, COVID-19 is highly evolved & has a number of ways to switch off the cell's immune function. So I see vaccines facing an uphill battle in order to succeed.
 
JacksinPA said:
There are around 100 COVID-19 vaccines in development. Some may work, many will not. And we have no way to determine how long the immunity lasts. Like the ordinary flu shot, they have to reformulate the vaccine every year to account for different strains. The COVID-19 spike protein, which many of these experimental vaccines are targeting, is known to mutate = different strains. I have no info on whether the camostat target TMPRSS2 enzyme also mutates, but camostat & related drugs are relatively simple molecules that can be manipulated chemically to provide a family of anti-viral drugs to be effective against mutant enzymes. All of this will have to be worked out in animal & clinical trials.

One problem with the vaccine approach is that it works after the virus has entered the cell, COVID-19 is highly evolved & has a number of ways to switch off the cell's immune function. So I see vaccines facing an uphill battle in order to succeed.
Click to expand...

Vaccines offer a much better chance of success than an antiviral.

We don’t even know the function of the protein camostat affects. That’s not good- off target effects will be tough to predict and a surprise when you go into Phase 3.
 
JacksinPA said:
Fauci has to be aware of this because it's i the open scientific literature.

Ono Pharmaceutical looks like a bargain: OPHLY (OTCMKTS) $8.89 -0.09 (-1.00%)
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I'm sure that Fauci is aware of it, as I'm sure he's aware of headlines like this: Moderna climbs 5% as Fauci calls its early COVID-19 vaccine data 'quite promising' (MRNA). Ono has been bouncing between $6-9 for years, although it has been as high as $15 (2016). Trump, though, can't control its output, as he can for Moderna or Gilead.
 
Threegoofs said:
Vaccines offer a much better chance of success than an antiviral.

We don’t even know the function of the protein camostat affects. That’s not good- off target effects will be tough to predict and a surprise when you go into Phase 3.
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That's not correct. See https://www.cell.com/cell/pdf/S0092-8674(20)30229-4.pdf which explains the whole process & its components, including comostat.

The spike protein of COVID-19 binds electrostatically to the ACE2 protein receptors which line our respiratory tract from nose to lungs. But it takes the enzyme TMPRSS2 to modify the spike protein in order for it to enter the cell. Comostat inhibits TMPRSS2, preventing the virus from entering the cell. And TMPRSS2 is a protease.
 
JacksinPA said:
That's not correct. See https://www.cell.com/cell/pdf/S0092-8674(20)30229-4.pdf which explains the whole process & its components, including comostat.

The spike protein of COVID-19 binds electrostatically to the ACE2 protein receptors which line our respiratory tract from nose to lungs. But it takes the enzyme TMPRSS2 to modify the spike protein in order for it to enter the cell. Comostat inhibits TMPRSS2, preventing the virus from entering the cell. And TMPRSS2 is a protease.
Click to expand...

And...what does TMPRSS2 do physiologically?

It exists for a reason.

We don’t know why.

That’s a risk.

Again...compelling mechanisms exist in every single drug candidate. Most fail.
 
Threegoofs said:
And...what does TMPRSS2 do physiologically?

It exists for a reason.

We don’t know why.

That’s a risk.

Again...compelling mechanisms exist in every single drug candidate. Most fail.
Click to expand...

It seems that the primary function of that enzyme involves the prostate:

UniProtKB - O15393 (TMPS2_HUMAN)Basket

Plasma membrane-anchored serine protease that participates in proteolytic cascades of relevance for the normal physiologic function of the prostate (PubMed:25122198). Androgen-induced TMPRSS2 activates several substrates that include pro-hepatocyte growth factor/HGF, the protease activated receptor-2/F2RL1 or matriptase/ST14 leading to extracellular matrix disruption and metastasis of prostate cancer cells (PubMed:15537383, PubMed:26018085, PubMed:25122198). In addition, activates trigeminal neurons and contribute to both spontaneous pain and mechanical allodynia (By similarity).By similarity3 Publications
(Microbial infection) Facilitates human coronaviruses SARS-CoV and SARS-CoV-2 infections via two independent mechanisms, proteolytic cleavage of ACE2 receptor which promotes viral uptake, and cleavage of coronavirus spike glycoproteins which activates the glycoprotein for host cell entry (PubMed:24227843, PubMed:32142651). Proteolytically cleaves and activates the spike glycoproteins of human coronavirus 229E (HCoV-229E) and human coronavirus EMC (HCoV-EMC) and the fusion glycoproteins F0 of Sendai virus (SeV), human metapneumovirus (HMPV), human parainfluenza 1, 2, 3, 4a and 4b viruses (HPIV). Essential for spread and pathogenesis of influenza A virus (strains H1N1, H3N2 and H7N9); involved in proteolytic cleavage and activation of hemagglutinin (HA) protein which is essential for viral infectivity.

If you are on death's door from a severe COVID-19 infection, I would think the last thing you would be concerned about is your prostate. I would expect your body would return to normal function following convalescence.
 
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JacksinPA said:
It seems that the primary function of that enzyme involves the prostate:

UniProtKB - O15393 (TMPS2_HUMAN)Basket

Plasma membrane-anchored serine protease that participates in proteolytic cascades of relevance for the normal physiologic function of the prostate (PubMed:25122198). Androgen-induced TMPRSS2 activates several substrates that include pro-hepatocyte growth factor/HGF, the protease activated receptor-2/F2RL1 or matriptase/ST14 leading to extracellular matrix disruption and metastasis of prostate cancer cells (PubMed:15537383, PubMed:26018085, PubMed:25122198). In addition, activates trigeminal neurons and contribute to both spontaneous pain and mechanical allodynia (By similarity).By similarity3 Publications
(Microbial infection) Facilitates human coronaviruses SARS-CoV and SARS-CoV-2 infections via two independent mechanisms, proteolytic cleavage of ACE2 receptor which promotes viral uptake, and cleavage of coronavirus spike glycoproteins which activates the glycoprotein for host cell entry (PubMed:24227843, PubMed:32142651). Proteolytically cleaves and activates the spike glycoproteins of human coronavirus 229E (HCoV-229E) and human coronavirus EMC (HCoV-EMC) and the fusion glycoproteins F0 of Sendai virus (SeV), human metapneumovirus (HMPV), human parainfluenza 1, 2, 3, 4a and 4b viruses (HPIV). Essential for spread and pathogenesis of influenza A virus (strains H1N1, H3N2 and H7N9); involved in proteolytic cleavage and activation of hemagglutinin (HA) protein which is essential for viral infectivity.

If you are on death's door from a severe COVID-19 infection, I would think the last thing you would be concerned about is your prostate. I would expect your body would return to normal function following convalescence.
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It’s not in the lungs to help the prostate.

There’s clearly a function here that is unknown.

Sometimes that’s fine. Sometimes it’s not.
 
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