Can Remdesivir (GS-5734) Strongly Inhibit COVID19 Replication?

 

Remdesivir (GS-5734) can Strongly Inhibit Coronavirus Replication

This is a small science article that I published on Knowledge Planet · Knowledge Hot last July. It was introduced that Remdesivir (GS-5734), an Ebola treatment drug (in clinical trials), can strongly inhibit coronavirus replication. SARS and MERS are also afraid of "magic medicine"

Continuing from the previous article [Shocking rescue of Ebola hemorrhagic fever "recovered" patients with recurrent encephalitis-"magic medicine" and "black and white"

 

 Is MERS (Middle East Respiratory Syndrome) still endemic?

SARS, or "SARS," the 2003 outbreak made people across the world "come together", and MERS (Middle East Respiratory Syndrome), which began to appear in Saudi Arabia in 2012, is still endemic. And it was imported into our country by a Korean.

 

In response to SARS, the method used by Academician Zhong Nanshan and his team was high-dose hormone shock therapy when they saved people. Although people can be rescued, hormone therapy has many sequelae. So what are the good treatments for these two very contagious coronavirus infections?

 

The Ebola treatment chemical small molecule drug GS-5734, which was introduced last time in ongoing clinical trials, was found to have a very good inhibitory effect against the coronavirus. A brief introduction is as follows.

 

First, human lung epithelial cells were used to expand and culture MERS-CoV, and it was found that the IC50 of GS-5734 was 0.03μM, which is a very low concentration.

 

After all, cell culture cannot completely simulate the natural infection process of the virus. The author then adopted the organoid cell culture system (HAE), which is a liquid-gas biphasic human primary bronchial cell culture environment to simulate the human respiratory tract.

In this system, the author found that GS-5734 has a good inhibitory effect on the replication of SARS-CoV and MERS-CoV.

 

Before the emergence of SARS-CoV, why coronavirus was not regarded as much attention by the virology? 

Before the emergence of SARS-CoV, the coronavirus was not regarded as much attention by the virology community, because the diseases caused by such viruses are generally common colds, not major diseases.

In addition, there are some viruses that do not infect humans in nature, including bats. After the emergence of SARS and MERS, people are paying more and more attention to these viruses. 

What is the inhibitory effect of the new GS-5734 on these viruses?

It can be seen that the inhibitory effect of these viruses on HAE is also very good.

Also Refer: Vaccine Development Encyclopedia

In the mouse model, the author gave the drug one day in advance and then was infected with SARS-CoV. It can be found that giving GS-5734 in advance has a certain preventive effect.

In terms of treatment, if the virus is first infected and then administered, the symptoms of the disease can be reduced in mice.

As mentioned earlier, because GS-5734 can be triphosphorylated in the body, it is incorporated into the newly synthesized RNA strand of the virus as a substrate of the viral RdRp, thereby interrupting the synthesis of the viral genome. 

In the process of using this drug, will the coronavirus mutate and develop resistance?

This is for sure, there have been studies that have identified several mutation sites. In the NSP12 gene encoded by the virus RdRp, the presence of F476L and V553L will reduce the sensitivity to GS-5734, but the replication efficiency of this mutant virus itself is also relatively low.

 

In addition, some people say that the effect of this drug in clinical trials of Ebola is not good, but it is not bad, but the effect of human-derived antibodies in the same period is too good, which seems to be bad. 

But even so, the effect of Remdesivir (GS-5734) in the treatment of Ebola, the fatality rate of the patients is still similar to the effect of the previously famous ZMAPP, so it is still very promising.

 

The results of this clinical experiment published in NEJM have also been popularized on the planet-https://t.zsxq.com/BUFyrR3

However, possibly, this drug may have a better effect on the current new type of coronavirus, because it is also a disease of coronavirus infection-feline infectious peritonitis (feline transmission). 

The therapeutic effect of GS-5734 parent drug GS-441524 is It is very obvious that most cats sentenced to death can be rescued by GS-441524.

 

How is coronavirus infection treated?

Coronavirus infection, if it is the common cold before, almost no treatment is needed.

But for severe cases of SARS and MERS, many attempts were made under the conditions at the time.

The most prominent symptom is pneumonia, and viral pneumonia, in many cases, is completely new. After the body's immune system has never seen a pathogen that infects the respiratory system, the immune system passes through the alveoli after being mobilized by the blood circulation. 

The release of some cytokines can cause acute inflammation. These cytokines can recruit more immune cells, produce more cytokines, and can attack virus-infected cells. 

After these cells die, some substances released can amplify the inflammatory response. Therefore, people are unable to support because of this aggravated immune response, which is a typical acute immune pathological injury.

 

In addition to the new crown, the influenza virus that is circulating in winter often causes such consequences. Therefore, this time the new crown should also help everyone increase their awareness of influenza prevention.

 

How to treat it? During SARS, Academician Zhong Nanshan used glucocorticoids for shock therapy. Glucocorticoid is an immunosuppressant, so it is well understood that it can relieve white lungs. However, in turn, the immune response itself kills the virus. 

After the immune response is suppressed, the replication of the virus will rebound again, which is a double-edged sword. And the use of exogenous hormones will have many side effects, such as bone necrosis.

Generally speaking, the most important thing is supportive therapy, bed rest, and oxygen supplementation if the respiratory system is damaged.

There are currently no antiviral drugs specifically targeted at the coronavirus, but previous studies have had some results. This time, we can actually take this opportunity to design a trial for clinical verification.

 

Such as protease inhibitors against HIV, Lopinavir and Ritonavir. This is a small molecule drug that has been on the market. It was found to have an effect as early as the SARS epidemic, and was later used during the MERS epidemic. 

 

Are there no in vivo experimental results for coronavirus?

The other is a powerful coronavirus inhibitor Remedesivir/GS-5734, but there are no in vivo experimental results for coronavirus, but the effect of in vitro experiments is very good, and the effective half of the inhibition rate is at the nanomole/nM level. Very little can work. This drug is currently in Phase 2 clinical trials of Ebola. I just shared the results of that study in the ball a while ago.

Regarding Remedesivir/GS-5734, it is suggestible that the Health Commission/CDE negotiate with Gilead to see if clinical trials of the new crown can be directly carried out. Because this drug has a very good effect in inhibiting coronavirus in vitro, the same parent drug GS-441524 is also a specific drug for treating infectious peritonitis in cats (coronavirus disease in cats). Moreover, the EBOV clinical trials are also on the safe side.

In the end, experts were very impressed by SARS when an old expert was infected and strongly demanded that he be a test subject, inject the plasma of recovered patients into his body, and he recovered. This type of therapy is a convalescent serum therapy.

If an infected person recovers, there will be antibodies in his blood, that is, immunoglobulin, and because he has just recovered, the proportion of antibodies against the newly infected virus is very high at this time, so this is a clear and effective treatment. 

We may hope that the current clinics and treatment units have planned voluntary blood donations to recovered patients, and reserve the serum as a life-saving medicine for critically ill patients.

The new crown diagnosis and treatment plan issued a few days ago also clearly mentioned these treatment methods-bed rest, strengthen supportive treatment. 

Oxygen therapy according to changes in oxygen saturation. Short-term use of corticosteroids for breathing difficulties and chest imaging conditions.

Unfortunately, the second edition deletes the antiviral treatment of lopinavir/ritonavir mentioned in the first edition twice a day, and does not mention the special use of convalescent serum. It does mention breathing support and circulatory support (even EMCO).

 

Convalescent serum has many shortcomings, so I hope that technology can be changed. After convalescent patients donate blood, B cells are separated and sequenced, and antibody sequences are directly obtained for exogenous expression. This can avoid some cases of foreign immune rejection.

 

 

Further reading:

 

1. Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses

 

https://stm.sciencemag.org/content/9/396/eaal3653

 

2. Coronavirus Susceptibility to the Antiviral Remdesivir (GS-5734) Is Mediated by the Viral Polymerase and the Proofreading Exoribonuclease.

Author's Bio

Name: Gwynneth May

Educational Qualification: MBBS, MD (Medicine) Gold Medalist

Profession: Doctor

Experience: 16 Years of Work Experience as a Medical Practitioner

About Me