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.

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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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Laroxe
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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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