Remdesivir - a possible treatment for COVID-19?

  • #1
Andrew Mason
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For anyone following Remdesivir as a treatment for COVID 19:
Remdesivir is "intracellularly metabolized to an analogue of adenosine triphosphate that inhibits viral RNA polymerases". I am not sure whether this disables the RNA polymerase from functioning or whether it causes RNA polymerase to produce defective viral mRNA transcript (eg. by inserting a few of these modified adenosine molecules instead of normal adenosine during transcription). In any event, this prevents replication of the virus by inhibiting RNA polymerase function.

This is not my area, but seems to me that to be really effective, such a drug has to be able to selectively enter cells i.e. enter only cells infected by a virus. Otherwise, the drug would enter healthy cells and interfere with normal RNA transcription and damage or kill them. If Remdesivir could be modified to somehow identify cells infected by SARS-CoV-2 and enter only those cells, there could be huge potential for this drug. I would appreciate hearing from others who have a background in molecular biology.

AM
 
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  • #2
Ygggdrasil
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SARS-CoV-2, the virus that causes COVID-19, has an RNA genome. Therefore, to copy its RNA genome in order to make new copies of the virus, the virus requires an RNA-dependent RNA polymerase (RdRP)—that is, an enzyme that makes RNA by reading off of an RNA template. The RdRP enzyme is encoded by the viral genome, so remdesivir targets a protein present only in virally-infected cells, not an enzyme present in all human cells.

Furthermore, the viral RdRP enzyme is very different from the DNA-dependent RNA polymerases that are present inside normal human cells and involved in transcription (copying the genetic information from DNA to mRNA so that information could be translated into protein by the ribosome). AFAIK, there are no functional RNA-dependent RNA polymerases encoded in the human genome.
 
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  • #3
Andrew Mason
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SARS-CoV-2, the virus that causes COVID-19, has an RNA genome. Therefore, to copy its RNA genome in order to make new copies of the virus, the virus requires an RNA-dependent RNA polymerase (RdRP)—that is, an enzyme that makes RNA by reading off of an RNA template. The RdRP enzyme is encoded by the viral genome, so remdesivir targets a protein present only in virally-infected cells, not an enzyme present in all human cells.

Furthermore, the viral RdRP enzyme is very different from the DNA-dependent RNA polymerases that are present inside normal human cells and involved in transcription (copying the genetic information from DNA to mRNA so that information could be translated into protein by the ribosome). AFAIK, there are no functional RNA-dependent RNA polymerases encoded in the human genome.
Thanks for your very helpful explanation.

So does that mean that the intracellular adenosine analogue that Remdesivir delivers is taken up only by the viral RNA dependent polymerase (RdRP) and not the host cell's RNA polymerase nor in its RNA transcripts? If so, how would that occur?

AM
 
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Ygggdrasil
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So does that mean that the intracellular adenosine analogue that Remdesivir delivers is taken up only by the viral RNA dependent polymerase (RdRP) and not the host cell's RNA polymerase nor in its RNA transcripts? If so, how would that occur?
Even though the SARS-CoV-2 RdRP and cellular RNA polymerases perform similar chemical reactions, the structures of the active sites are slightly different, and chemists can exploit these differences to design drugs that can bind to the RdRP but not to cellular RNA polymerases. This ability to discriminate between similar types of active sites enables a number of important drugs, such as the nucleoside analogs used as reverse transcriptase inhibitors in anti-HIV therapy (which can bind to the active site of HIV reverse transcriptase, but not similar cellular DNA polymerases) or kinase inhibitor drugs like Gleevec used in anti-cancer therapy (which can selectively bind to the active sites of specific cellular protein kinases without binding to all of the various protein kinases in the body).

Here is a recent paper with a lot more information about how remdesivir binds to and inhibits the viral RdRP enzyme: https://science.sciencemag.org/content/368/6498/1499
 
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Andrew Mason
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Even though the SARS-CoV-2 RdRP and cellular RNA polymerases perform similar chemical reactions, the structures of the active sites are slightly different, and chemists can exploit these differences to design drugs that can bind to the RdRP but not to cellular RNA polymerases. This ability to discriminate between similar types of active sites enables a number of important drugs, such as the nucleoside analogs used as reverse transcriptase inhibitors in anti-HIV therapy (which can bind to the active site of HIV reverse transcriptase, but not similar cellular DNA polymerases) or kinase inhibitor drugs like Gleevec used in anti-cancer therapy (which can selectively bind to the active sites of specific cellular protein kinases without binding to all of the various protein kinases in the body).

Here is a recent paper with a lot more information about how remdesivir binds to and inhibits the viral RdRP enzyme: https://science.sciencemag.org/content/368/6498/1499
Thanks so much for your very clear response and link. The article appears to have been published today so it is about as up-to-date as possible.

It appears that the Remdesivir ATP molecule (RTP) with its modified adenosine attaches to the RNA primer strand at the first base pair which terminates further RNA transcription. So that answers my initial question.

Since Remdesivir was designed as a general anti-viral and seemed to work well on SARS-CoV which has a slightly different shaped RNA polymerase than SARS-CoV-2, a bit of tweaking of the drug shape/binding sites might be all that is needed for a really effective treatment of COVID-19.

I will take some time to go through the article over the weekend. This approach to drug "engineering" is really fascinating stuff.

AM
 
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Ygggdrasil
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Thanks so much for your very clear response and link. The article appears to have been published today so it is about as up-to-date as possible.
For such a rapidly moving field as COVID-19 research, the actual published scientific literature is actually a bit out of date. For example, the Science paper that was just published today was first released as a (non-peer reviewed) pre-print on April 9. So, even for research that is quite timely, the published scientific literature can be months behind (more typically, the peer review process takes 0.5-1+ years, inserting further delays between when a research finding is first made and when it is formally published).

Since Remdesivir was designed as a general anti-viral and seemed to work well on SARS-CoV which has a slightly different shaped RNA polymerase than SARS-CoV-2, a bit of tweaking of the drug shape/binding sites might be all that is needed for a really effective treatment of COVID-19.
Yes, it is likely that remdesivir could be modified to have better activity against SARS-CoV-2 (IIRC, remdesivir was originally designed against the Ebola virus). However, it would likely take quite a long time to optimize the drug and for the drug to go through clinical trials before it could be approved for widespread use in patients. Such a drug would likely not be able to help with the current outbreak but would help if vaccination cannot fully eradicate the disease or if we encounter a new zoonotic coronavirus in the future (with three new coronaviruses emerging in the past 20 years, we are almost certain to see other new coronaviruses in the future).
 
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Andrew Mason
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Here is a recent paper with a lot more information about how remdesivir binds to and inhibits the viral RdRP enzyme: https://science.sciencemag.org/content/368/6498/1499
That paper examines the structure of the RdRp molecule and the way that Remdesivir interferes with the RdRp function in replicating the viral RNA genome. The authors mention another similar drug EIDD-2801 that shows even greater effectiveness in blocking viral RNA replication in SARS-CoV-2:

"In particular, EIDD-2801 has been shown to be 3 to 10 times as potent as remdesivir in blocking SARS-CoV-2 replication (36). The N4 hydroxyl group off the cytidine ring forms an extra hydrogen bond with the side chain of K545, and the cytidine base also forms an extra hydrogen bond with the guanine base from the template strand. These two extra hydrogen bonds may explain the apparent higher potency of EIDD-2801 in inhibiting SARS-CoV-2 replication."

EIDD-2801 is just entering Phase 2 trials

AM
 
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Andrew Mason
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One possible problem with the remdesivir approach is that it functions only after the virus has infected the cell. Since lung epithelial cells express multiple ACE2 receptors a cell can be attacked by several viruses and unless the drug is 100% effective in stopping replication the virus may still proliferate and cause a lot of damage.

However.... used in conjunction with another imperfect drug that reduces the virus' ability to get into cells, might provide an effective therapy for COVID.

AM
 
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  • #9
Andrew Mason
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It looks like the Trump administration thinks remdesivir may be a cure for COVID-19. They have just bought up the entire world supply for the next 3 months. That's 500,000 doses. Europe is a tad upset. Someone should tell the EU to approach Merck and Ridgebackbio to purchase supplies of EIDD-2801, which Ridgeback says it has been producing. Remdesivir is injected whereas EIDD-2801 is taken as a pill so EIDD-2801 is easier to deploy and, apparently, easier to manufacture. The owners of Ridgebackbio say they will have 1 million doses available by fall.

AM
 
  • #10
Ygggdrasil
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One possible problem with the remdesivir approach is that it functions only after the virus has infected the cell. Since lung epithelial cells express multiple ACE2 receptors a cell can be attacked by several viruses and unless the drug is 100% effective in stopping replication the virus may still proliferate and cause a lot of damage.

However.... used in conjunction with another imperfect drug that reduces the virus' ability to get into cells, might provide an effective therapy for COVID.

AM
At least for some viruses, nucleoside analogues can function to prophylacticaly prevent infections. For example, Truvada, a mixture of the nucleotide analogue tenofovir and the nucleoside emtricitabine, is FDA approved as a pre-exposure prophylaxis (PrEP) medicine to prevent HIV infection.

Of course, retroviruses are different than coronaviruses, so the situation could be very different. However, there is data from monkeys that prophylactic administration of remdesivir can prevent disease from the MERS coronavirus (https://www.pnas.org/content/117/12/6771):

Abstract:
The continued emergence of Middle East Respiratory Syndrome (MERS) cases with a high case fatality rate stresses the need for the availability of effective antiviral treatments. Remdesivir (GS-5734) effectively inhibited MERS coronavirus (MERS-CoV) replication in vitro, and showed efficacy against Severe Acute Respiratory Syndrome (SARS)-CoV in a mouse model. Here, we tested the efficacy of prophylactic and therapeutic remdesivir treatment in a nonhuman primate model of MERS-CoV infection, the rhesus macaque. Prophylactic remdesivir treatment initiated 24 h prior to inoculation completely prevented MERS-CoV−induced clinical disease, strongly inhibited MERS-CoV replication in respiratory tissues, and prevented the formation of lung lesions. Therapeutic remdesivir treatment initiated 12 h postinoculation also provided a clear clinical benefit, with a reduction in clinical signs, reduced virus replication in the lungs, and decreased presence and severity of lung lesions. The data presented here support testing of the efficacy of remdesivir treatment in the context of a MERS clinical trial. It may also be considered for a wider range of coronaviruses, including the currently emerging novel coronavirus 2019-nCoV.
 
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Andrew Mason
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At least for some viruses, nucleoside analogues can function to prophylacticaly prevent infections. For example, Truvada, a mixture of the nucleotide analogue tenofovir and the nucleoside emtricitabine, is FDA approved as a pre-exposure prophylaxis (PrEP) medicine to prevent HIV infection.

Of course, retroviruses are different than coronaviruses, so the situation could be very different. However, there is data from monkeys that prophylactic administration of remdesivir can prevent disease from the MERS coronavirus (https://www.pnas.org/content/117/12/6771):
Thanks for the link.

It seems, though, that the prophylactic effect is not due to remdesivir preventing the virus getting into the cell but is the result of getting a headstart on the virus by getting the remdesivir nucleotide analogue RTP into the cells so that when the virus enters the cells the RTP is already there and able to insert itself into the viral RNA polymerase, stopping viral replication from the outset of infection. If remdesivir has no serious side effects it may be able to function as a prophylactic but at $2,000+ per dose and the fact that it has to be taken intravenously may make that somewhat impractical.

The HIV drug cocktail approach is to attack the HIV virus at several stages in its replication cycle, including impeding its ability to enter cells. Although, as you say, the HIV is a retrovirus that does not use an RNA transcriptase, the use of a multi-stage approach to attacking the virus has been very effective in controlling HIV and preventing AIDS. It seems to be a reasonable way of approaching SARS-CoV-2, which has at least 4 stages where small molecule drug intervention could be effective:

1593658795939.png


This article, just published yesterday, seems to suggest that approach might work with SARS-CoV-2. Some of these drugs that seem to work to stop SARS-CoV-2 replication are already approved for HIV and other viruses, so it may be relatively quick to get FDA approval. I wonder if anyone has looked at COVID-19 stats for people taking anti-HIV medication......

AM
 
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Ygggdrasil
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Thanks for the link.

It seems, though, that the prophylactic effect is not due to remdesivir preventing the virus getting into the cell but is the result of getting a headstart on the virus by getting the remdesivir nucleotide analogue RTP into the cells so that when the virus enters the cells the RTP is already there and able to insert itself into the viral RNA polymerase, stopping viral replication from the outset of infection. If remdesivir has no serious side effects it may be able to function as a prophylactic but at $2,000+ per dose and the fact that it has to be taken intravenously may make that somewhat impractical.
Agreed. An IV drug is not very practical as a prophylactic.

The HIV drug cocktail approach is to attack the HIV virus at several stages in its replication cycle, including impeding its ability to enter cells.
In general, HIV drug cocktails are designed to target multiple stages of the HIV replication cycle (such as those that combine reverse transcriptase inhibitors with protease inhibitors). However, the prophylactic drug Truvada combines two different reverse transcriptase inhibitors, so it is only targeting one step of the HIV life cycle (which occurs after viral entry).

This article, just published yesterday, seems to suggest that approach might work with SARS-CoV-2. Some of these drugs that seem to work to stop SARS-CoV-2 replication are already approved for HIV and other viruses, so it may be relatively quick to get FDA approval. I wonder if anyone has looked at COVID-19 stats for people taking anti-HIV medication......
Note that the figure you posted is based on the assumed mechanism of action of drugs under investigation to treat COVID-19. Of the drugs listed, only one (remdesivir) has strong evidence of efficacy. Others, in particular hydroxychloroquine and the protease inhibitors (lopinavir and danoprevir), have had various studies conclude that they are not effective at treating COVID-19. Indeed, the CDC recommends against the use of hydroxychloroquine as well as lopinavir and other HIV protease inhibitors for COVID-19: https://www.covid19treatmentguidelines.nih.gov/antiviral-therapy/
 
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Andrew Mason
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Note that the figure you posted is based on the assumed mechanism of action of drugs under investigation to treat COVID-19. Of the drugs listed, only one (remdesivir) has strong evidence of efficacy. Others, in particular hydroxychloroquine and the protease inhibitors (lopinavir and danoprevir), have had various studies conclude that they are not effective at treating COVID-19. Indeed, the CDC recommends against the use of hydroxychloroquine as well as lopinavir and other HIV protease inhibitors for COVID-19: https://www.covid19treatmentguidelines.nih.gov/antiviral-therapy/
All good points.

My purpose in posting the diagram was to just show the points at which drug intervention could occur, not to suggest the drugs to be used. APN001, which delivers an extra-cellular recombinant human ACE2 receptor, might assist in step 1, for example, in reducing the rate of entry of the virus into cells. When combined with some of the viral RNA polymerase inhibitors (remdesivir, EIDD-2801 or the five drugs listed in the Science Daily article published June 30) the combination might be much more effective than any individual drug.

AM
 

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