Various approaches to new anti-viral drugs to treat COVID-19

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Andrew Mason
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There have been a number of approaches taken in developing drugs to combat the SARS-CoV-2 virus:

1. Interfering with the viral RdRP polymerase so the virus cannot replicate its RNA (Remdesivir, EIDD-2801, Galidesivir) (see: this thread)

2. Preventing the virus from attaching to the ACE2 receptor on a cell: hrsACE2 or APN01 (see: this thread)

3. After the virus attaches to the ACE2 receptor, preventing the virus from entering the cell by preventing viral-membrane and cell-membrane fusion.

4. Protease inhibitors that prevent the viral proteases from cutting the peptide chains after translation from viral RNA. These cuts result in essential viral proteins, so blocking their function prevents the viral reproduction.

With respect to 3., this recent paper explains the mechanism by which SARS-CoV virus-cell membrane fusion occurs and, using computer modelling, provides a design for a new protein to block this process:

In silico design of antiviral peptides targeting the spike protein of SARS-CoV-2 said:
"Based on the HR2 region of SARS-CoV-2 and the use of biomolecular simulation, we have designed an HR2-based antivirus peptide with higher binding energy to HR1, thus can prevent the SARS-CoV-2 membrane fusion. When HR2-based peptide is pulled out and dissociates from HR1, more hydrogen bonds will form to prevent HR2 dissociation (Fig. 5d). Our findings provide a possible treatment for SARS-CoV-2 infection and also prepare for future clinical application research for SARS-CoV-2 therapy. "

Regarding 4., this recent paper suggests that the "3C-like protease" in SARS-CoV-2 would be a good target. The 3C protease is a target of some HIV anti-viral drugs such as Lopinavir, Tipranavir, Ataznavir, and Amprenavir, all of which are already FDA approved.

This recent paper, which was independent of the previous paper, used computer models to determine the most effective protease inhibitor for SARS-CoV-2 and predicts that Lopinavir-Ritonavir, Tipranavir, Raltegravir - all protease inhibitor drugs for treatment of HIV - should be the best three out of more than 75 candidate drugs screened.

AM
 
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Ygggdrasil
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Regarding 4., this recent paper suggests that the "3C-like protease" in SARS-CoV-2 would be a good target. The 3C protease is a target of some HIV anti-viral drugs such as Lopinavir, Tipranavir, Ataznavir, and Amprenavir, all of which are already FDA approved.

This recent paper, which was independent of the previous paper, used computer models to determine the most effective protease inhibitor for SARS-CoV-2 and predicts that Lopinavir-Ritonavir, Tipranavir, Raltegravir - all protease inhibitor drugs for treatment of HIV - should be the best three out of more than 75 candidate drugs screened.

Although HIV protease and the SARS-CoV-2 proteases are both proteases, they work quite differently. HIV protease is an aspartyl protease that uses aspartate residues to activate and position water molecules for hydrolysis of the peptide bond. In contrast, the SARS-CoV-2 proteases are cysteine proteases that use the thiol moiety of a cysteine residue as the nucleophile for cleaving the peptide bond of its substrate. Based on the very different mechanisms of action, I would not expect inhibitors of HIV protease to be particularly effective against the SARS-CoV-2 proteases. Not surprisingly, clinical studies of HIV proteases have shown that they are not effective at treating COVID-19. Indeed, the NIH recommends against using Lopinavir/ritonavir or other HIV protease inhibitors for treating COVID-19 patients. That the computational methods predict Lopinavir-Ritonavir as a top hit does not inspire confidence in the computational methods.

There have been recent drug screening efforts aimed at identifying new molecules that can inhibit the SARS-CoV-2 proteases (e.g. see this paper for the main protease/3C-like protease and this paper for the Papain-like protease), though it will likely take a long time for new molecules like these to advance to clinical trials.

-------------------------------

In addition to the strategies you outlined, there are a few other strategies drugmakers are pursuing to develop therapeutics for COVID-19.

5) Antibody therapy. The idea here is that antibodies will bind the SARS-CoV-2 viruses and help the immune system to inactivate them, mimicking the body's own natural adaptive immune response. One potential source of antibodies is convalescent plasma, though it would be difficult to obtain large quantities for widespread use. Monoclonal antibodies against SARS-CoV-2, however, could be produced at a large scale and treatments based on mAbs have recently shown much promise against other viruses like Ebola. Animal studies for mAb cocktails look promising. Scientists have also recently developed much more stable versions of antibodies that could potentially be aerosolized into a nasal spray (though no clinical tests of this idea have been done yet). A related idea would employ interferons treatment to help boost the immune response against the virus (the NIH is currently running a phase III trial to test interferons in combination with remdesivir as a COVID-19 treatment).

6) Immunosuppressants. A major source of mortality from SARS-CoV-2 infection is the "cytokine storm" that gets unleashed by the body's immune system in later stages of the infection. While these drugs don't directly target the virus, they could reduce mortality by alleviating the damage done by the virus. Indeed, dexamethosone, a widely available steroid that can suppress the immune system, has been shown to reduce mortality in severe COVID-19 cases. Other similar approaches include cytokine inhibitors (such as IL-6 inhibitors, though recent trials suggested that these were not effective). Of course, one needs to be careful as administering immunosuppresants too early in the course of a viral infection could worsen the infection.
 
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I know on the world community grid, which is often used in drug screening they describe how with sufficient computing power scientists can screen thousands of compounds for a good match to various target proteins on the virus. Its described as a way of identifying the compounds with the greatest chance of having an effect, these can then be subject to more detailed examination. Basically its just a way of trying to focus the research on what might be the best bets, they can flag up quite a number of compounds really but no one really thinks they are reliable indicators of effectiveness.
Just for interest there has been disappointing news about the use of convalescent plasma , a study in the BMJ found "Convalescent plasma was not associated with a reduction in progression to severe covid-19 or all cause mortality. "
https://www.bmj.com/content/371/bmj.m3939
 
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Astronuc
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Researchers at the University of Liverpool have shown how SARS-CoV-2 viral proteases attack the host cell, and how this can be targeted to stop virus replication in cell culture using existing drugs.
https://phys.org/news/2021-09-inhibiting-sars-cov-proteases-block-infection.html
The new findings, published today in Nature Communications, offer a powerful resource to understand proteolysis in the context of viral infection, and to inform the development of targeted strategies to inhibit the virus that causes COVID-19.
. . .
Both viral and cellular proteases play a crucial role in SARS-CoV-2 replication, and inhibitors targeting proteases have already shown success at inhibiting SARS-CoV-2 in cell culture models.
. . .
Both Bafetinib (an experimental cancer drug) and Sorafenib (an approved drug used to treat kidney and liver cancer) showed SARS-CoV-2 inhibition at concentrations that did not result in cytotoxicity in a human cell line model of infection.

So, protease-inhibitors?
 
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Andrew Mason
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There have been a number of approaches taken in developing drugs to combat the SARS-CoV-2 virus:
....

4. Protease inhibitors that prevent the viral proteases from cutting the peptide chains after translation from viral RNA. These cuts result in essential viral proteins, so blocking their function prevents the viral reproduction.

Regarding 4., this recent paper suggests that the "3C-like protease" in SARS-CoV-2 would be a good target. The 3C protease is a target of some HIV anti-viral drugs such as Lopinavir, Tipranavir, Ataznavir, and Amprenavir, all of which are already FDA approved.

This recent paper, which was independent of the previous paper, used computer models to determine the most effective protease inhibitor for SARS-CoV-2 and predicts that Lopinavir-Ritonavir, Tipranavir, Raltegravir - all protease inhibitor drugs for treatment of HIV - should be the best three out of more than 75 candidate drugs screened.

AM
Researchers at the University of Liverpool have shown how SARS-CoV-2 viral proteases attack the host cell, and how this can be targeted to stop virus replication in cell culture using existing drugs.
https://phys.org/news/2021-09-inhibiting-sars-cov-proteases-block-infection.html


So, protease-inhibitors?
It looks like Pfizer has come up with an anti-viral protease inhibitor drug (Ritonavir or PF-07321332) for Covid-19 that is quite effective in preventing hospitalization if administered within 3 days from the onset of symptoms. Lopinavir-Ritonavir was the top candidate predicted by the computer analysis referred to above. I note from the clinical trial information that the Phase III trial was entitled:​
"AN INTERVENTIONAL EFFICACY AND SAFETY, PHASE 2/3, DOUBLE-BLIND, 2 ARM STUDY TO INVESTIGATE ORALLY ADMINISTERED PF 07321332/RITONAVIR COMPARED WITH PLACEBO IN NONHOSPITALIZED SYMPTOMATIC ADULT PARTICIPANTS WITH COVID-19 WHO ARE AT LOW RISK OF PROGRESSING TO SEVERE ILLNESS"​

Perhaps @Ygggdrasil or others may wish to comment on the apparent significance of these results.

As indicated above, Ritonavir takes a different approach than Remdesivir or Molnupiravir/EIDD2801. It appears to operate by blocking the "3C-like protease" after viral RNA translation. Could one realize, perhaps, an greater benefit to using a cocktail approach of using multiple anti-virals as we experienced with HIV?

AM
 
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Ygggdrasil
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It looks like Pfizer has come up with an anti-viral protease inhibitor drug (Ritonavir or PF-07321332) for Covid-19 that is quite effective in preventing hospitalization if administered within 3 days from the onset of symptoms. Lopinavir-Ritonavir was the top candidate predicted by the computer analysis referred to above. I note from the clinical trial information that the Phase III trial was entitled:​
"AN INTERVENTIONAL EFFICACY AND SAFETY, PHASE 2/3, DOUBLE-BLIND, 2 ARM STUDY TO INVESTIGATE ORALLY ADMINISTERED PF 07321332/RITONAVIR COMPARED WITH PLACEBO IN NONHOSPITALIZED SYMPTOMATIC ADULT PARTICIPANTS WITH COVID-19 WHO ARE AT LOW RISK OF PROGRESSING TO SEVERE ILLNESS"​

Perhaps @Ygggdrasil or others may wish to comment on the apparent significance of these results.

As indicated above, Ritonavir takes a different approach than Remdesivir or Molnupiravir/EIDD2801. It appears to operate by blocking the "3C-like protease" after viral RNA translation. Could one realize, perhaps, an greater benefit to using a cocktail approach of using multiple anti-virals as we experienced with HIV?

AM

The new anti-viral protease drug is PF-07321332. Ritonavir is an HIV protease inhibitor that is co-administered with PF-07321332. Ritonavir does not work by interacting with the SARS-CoV-2 protease to inhibit the enzyme; rather, ritonavir interacts with enzymes that would degrade PF-07321332 to extend the half-life of PF-07321332 in the body. From Pfizer's press release

PAXLOVID™ is an investigational SARS-CoV-2 protease inhibitor antiviral therapy, specifically designed to be administered orally so that it can be prescribed at the first sign of infection or at first awareness of an exposure, potentially helping patients avoid severe illness which can lead to hospitalization and death. PF-07321332 is designed to block the activity of the SARS-CoV-2-3CL protease, an enzyme that the coronavirus needs to replicate. Co-administration with a low dose of ritonavir helps slow the metabolism, or breakdown, of PF-07321332 in order for it to remain active in the body for longer periods of time at higher concentrations to help combat the virus.
https://www.pfizer.com/news/press-r...l-covid-19-oral-antiviral-treatment-candidate

Previous clinical trials of the Lopinavir-Ritonavir combination showed that they are ineffective against SARS-CoV-2, which is consistent with the major differences between HIV protease and the SARS-CoV-2 protease enzymes (discussed in my previous post):

A Trial of Lopinavir–Ritonavir in Adults Hospitalized with Severe Covid-19
https://www.nejm.org/doi/10.1056/NEJMoa2001282

CONCLUSIONS
In hospitalized adult patients with severe Covid-19, no benefit was observed with lopinavir–ritonavir treatment beyond standard care.

Because they target different viral enzymes, a cocktail of PF-07321332 and Molnupiravir would likely be a very good antiviral treatment for SARS-CoV-2. Here's a good source discussing the PF-07321332 news and its implications for the pandemic going forward:
https://www.science.org/content/blog-post/pfizer-s-good-news-world-s-good-news
 
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Andrew Mason
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Hi Ygggdrasil - thank-you for your insightful and helpful comments. I see that I read the "/" in "PF-07321332/Ritonavir" incorrectly as "or" rather than "and". And thanks for the link to the discussion of the PF-07321332 news.

AM
 
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Ygggdrasil
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I note from the clinical trial information that the Phase III trial was entitled:​
"AN INTERVENTIONAL EFFICACY AND SAFETY, PHASE 2/3, DOUBLE-BLIND, 2 ARM STUDY TO INVESTIGATE ORALLY ADMINISTERED PF 07321332/RITONAVIR COMPARED WITH PLACEBO IN NONHOSPITALIZED SYMPTOMATIC ADULT PARTICIPANTS WITH COVID-19 WHO ARE AT LOW RISK OF PROGRESSING TO SEVERE ILLNESS"​

Note that there was also another clinical trial run in parallel: " AN INTERVENTIONAL EFFICACY AND SAFETY, PHASE 2/3, DOUBLE-BLIND, 2-ARM STUDY TO INVESTIGATE ORALLY ADMINISTERED PF-07321332/RITONAVIR COMPARED WITH PLACEBO IN NONHOSPITALIZED SYMPTOMATIC ADULT PARTICIPANTS WITH COVID-19 WHO ARE AT INCREASED RISK OF PROGRESSING TO SEVERE ILLNESS."
https://clinicaltrials.gov/ct2/show/NCT04960202

According to Pfizer's press release, the drug showed strong benefits in the trial of patients who are at high risk of progressing to severe illness:
Pfizer Inc. (NYSE: PFE) today announced its investigational novel COVID-19 oral antiviral candidate,PAXLOVID™, significantly reduced hospitalization and death, based on an interim analysis of the Phase 2/3 EPIC-HR (Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients) randomized, double-blind study of non-hospitalized adult patients with COVID-19, who are at high risk of progressing to severe illness. The scheduled interim analysis showed an 89% reduction in risk of COVID-19-related hospitalization or death from any cause compared to placebo in patients treated within three days of symptom onset (primary endpoint); 0.8% of patients who received PAXLOVID™ were hospitalized through Day 28 following randomization (3/389 hospitalized with no deaths), compared to 7.0% of patients who received placebo and were hospitalized or died (27/385 hospitalized with 7 subsequent deaths). The statistical significance of these results was high (p<0.0001). Similar reductions in COVID-19-related hospitalization or death were observed in patients treated within five days of symptom onset; 1.0% of patients who received PAXLOVID™ were hospitalized through Day 28 following randomization (6/607 hospitalized, with no deaths), compared to 6.7% of patients who received a placebo (41/612 hospitalized with 10 subsequent deaths), with high statistical significance (p<0.0001). In the overall study population through Day 28, no deaths were reported in patients who received PAXLOVID™ as compared to 10 (1.6%) deaths in patients who received placebo.
https://www.pfizer.com/news/press-r...l-covid-19-oral-antiviral-treatment-candidate
 
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Ygggdrasil
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Here's a new strategy for antivirals: Therapeutic Interfering Particles

A defective viral genome strategy elicits broad protective immunity against respiratory viruses
https://www.sciencedirect.com/science/article/pii/S0092867421013386

Abstract:
RNA viruses generate defective viral genomes (DVG) that can interfere with replication of the parental wild-type virus. To examine their therapeutic potential, we created a DVG by deleting the capsid-coding region of poliovirus. Strikingly, intraperitoneal or intranasal administration of this genome, which we termed eTIP1, elicits an antiviral response, inhibits replication and protects mice from several RNA viruses, including enteroviruses, influenza and SARS-CoV-2. While eTIP1 replication following intranasal administration is limited to the nasal cavity, its antiviral action extends non-cell-autonomously to the lungs. eTIP1 broad-spectrum antiviral effects are mediated by both local and distal type I interferon responses. Importantly, while a single eTIP1 dose protects animals from SARS-CoV-2 infection, it also stimulates production of SARS-CoV-2 neutralizing antibodies that afford long-lasting protection from SARS-CoV-2 reinfection. Thus, eTIP1 is a safe and effective broad-spectrum antiviral generating short- and long-term protection against SARS-CoV-2 and other respiratory infections in animal models.

Identification of a Therapeutic Interfering Particle — a single-administration SARS-CoV-2 antiviral intervention with a high barrier to resistance
https://www.sciencedirect.com/science/article/pii/S0092867421013192

Abstract:
Viral-deletion mutants that conditionally replicate and inhibit wild-type virus (i.e., Defective Interfering Particles, DIPs) have long been proposed as single-administration interventions with high genetic barriers to resistance. However, theories predict that robust, therapeutic DIPs (i.e., Therapeutic Interfering Particles–TIPs) must conditionally spread between cells with R0>1. Here, we report engineering of TIPs that conditionally replicate with SARS-CoV-2, exhibit R0>1, and inhibit viral replication 10–100 fold. Inhibition occurs via competition for viral replication machinery and, a single administration of TIP RNA inhibits SARS-CoV-2 sustainably in continuous cultures. Strikingly, TIPs maintain efficacy against neutralization-resistant variants (e.g., B.1.351). In hamsters, both prophylactic and therapeutic intranasal administration of lipid-nanoparticle TIPs durably suppressed SARS-CoV-2 by 100 fold in the lungs, reduced pro-inflammatory cytokine expression, and prevented severe pulmonary edema. These data provide proof-of-concept for a class of single-administration antivirals that may circumvent current requirements to continually update medical countermeasures against new variants.
 
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Andrew Mason
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Thanks @Ygggdrasil.

So is the idea that if you put these DIP or TIP nano-particles (containing mRNA?) into the same cell that a Sars-CoV-2 virus has infected, the cell's translation machinery starts processing both and the virus parts get mixed up with the DIP/TIP parts so the virus cannot reproduce completely? Or is it just that the drain on the cell's translation machinery caused by the competition between virus and the DIPs slows the process - like a traffic jam brings a freeway to a halt?

If the DIPs/TIPs are not complete viruses how do they reproduce completely so they can spread (which seems to be a requirement)? Do they carry their own RNA dependent RNA Polymerase (RDRP)?

AM
 
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Ygggdrasil
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If the DIPs/TIPs are not complete viruses how do they reproduce completely so they can spread (which seems to be a requirement)? Do they carry their own RNA dependent RNA Polymerase (RDRP)?
I think the DIPs/TIPs are designed such that they won't replicate on their own as they are missing crucial components required for viral replication. However, when viruses infect the cells containing the DIP/TIP RNA, the virus provides the components necessary to produce more DIPs/TIPs, and these DIPs/TIPs spread to interfere with the infection of other cells.

So is the idea that if you put these DIP or TIP nano-particles (containing mRNA?) into the same cell that a Sars-CoV-2 virus has infected, the cell's translation machinery starts processing both and the virus parts get mixed up with the DIP/TIP parts so the virus cannot reproduce completely? Or is it just that the drain on the cell's translation machinery caused by the competition between virus and the DIPs slows the process - like a traffic jam brings a freeway to a halt?
Yes, the DIP/TIP nano-particles contain the mRNA encoding the defective viral genomes encapsulated in a lipid nanoparticle (similar to the mRNA vaccines) that allows them to enter cells. Unlike the vaccines, which are delivered via intramuscular injection, the DIP/TIPs are delivered intra-nasally to the tissues that are likely the first get infected by SARS-CoV-2.

I think it's not entirely clear what exactly is the mechanism for protection. The Xiao et al. paper seems to argue that their eTIPs work by activating the innate immune system to help fight off infection by SARS-CoV-2 and other similar respiratory viruses. The Chaturvedi et al paper, on the other hand, argues that the defective genomes produce by the TIPs are interfering with reproduction of functional SARS-CoV-2 genomes by stealing essential protein components that the genomes require for efficient reproduction. It is likely that both mechanisms contribute, though determining the extent to which these (and potentially other) mechanisms contribute to the inhibition of viral replication requires more research.
 
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The FDA has now authorized Pfizer's protease inhibitor drug as the first oral antiviral drug for the treatment of COVID-19:
The Food and Drug Administration on Wednesday authorized Paxlovid, a pill developed and made by Pfizer, as a treatment for Covid-19, a significant step in the battle against the SARS-CoV-2 virus.

The drug was authorized for use in people as young as 12 so long as they weigh at least 88 pounds.

The authorization of an oral antiviral to beat back Covid has been eagerly anticipated because such a medicine could reach large numbers of people infected with the virus and prevent them from becoming seriously ill or hospitalized. Existing medicines, such as monoclonal antibodies, must be given intravenously or as injections.

Still, initial supplies of Paxlovid will be limited. Pfizer has said it expects to produce more than 180,000 courses of the treatment this year. The company said Wednesday it now expects to provide 120 million courses by the end of 2022, up from 80 million previously, thanks in part to new contract manufacturers. Pfizer has contracted with the U.S. government to provide 10 million courses by the end of 2022 at a cost of $5.29 billion.
https://www.statnews.com/2021/12/22...to-treat-covid-19-in-patients-as-young-as-12/
 
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Astronuc
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Repeating myself from another discussion,
https://www.physicsforums.com/threa...le-treatment-for-covid-19.990773/post-6579473

https://www.fda.gov/news-events/pre...rizes-first-oral-antiviral-treatment-covid-19
Pfizer’s Paxlovid (nirmatrelvir tablets and ritonavir tablets, co-packaged for oral use) for the treatment of mild-to-moderate coronavirus disease (COVID-19) in adults and pediatric patients (12 years of age and older weighing at least 40 kilograms or about 88 pounds) with positive results of direct SARS-CoV-2 testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death. Paxlovid is available by prescription only and should be initiated as soon as possible after diagnosis of COVID-19 and within five days of symptom onset.

Nirmatrelvir (PF-07321332) is an antiviral medication developed by Pfizer which acts as an orally active 3CL protease inhibitor. https://en.wikipedia.org/wiki/Nirmatrelvir

Ritonvir is discussed here -
Ritonavir is an HIV protease inhibitor that is co-administered with PF-07321332. Ritonavir does not work by interacting with the SARS-CoV-2 protease to inhibit the enzyme; rather, ritonavir interacts with enzymes that would degrade PF-07321332 to extend the half-life of PF-07321332 in the body. From Pfizer's press release
and
https://en.wikipedia.org/wiki/Ritonavir
 

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