October 20, 2021

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How about the safety and mutagenicity of Merck oral COVID-19 drug?

How about the safety and mutagenicity of Merck oral COVID-19 drug?

How about the safety and mutagenicity of Merck oral COVID-19 drug?



How about the safety and mutagenicity of Merck oral COVID-19 drug?  What is the risk of mutagenesis?

Molnupiravirs is the first oral anti-coronavirus drug shown to be effective in clinical trials.

At that time, it mainly discussed its effectiveness, such as reducing the risk of hospitalization or death by nearly 50%.

The scope of application is patients in the early stages of infection.

It was also analyzed that oral medicine is an important supplement to the existing COVID-19 medical treatment but does not replace the vaccine.

However, the mutagenicity mentioned in the safety issue of this drug may make many people worry about it after reading it.

This article will focus on analyzing the antiviral principles of Molnupiravir, and then based on these principles, how to treat the safety of this drug, especially the risk of mutagenesis.


The structure and mechanism of the first oral drug for the COVID-19

Considering the safety of a drug is inseparable from the analysis of the chemical structure and mechanism of action of the drug. For antiviral drugs like Molnupiravir, the chemical structure and the mechanism of action are complementary.

From the structural point of view, Molnupiravir is a prodrug of ribonucleoside analogues. This sentence may be understood every word by everyone, but together it will be in the cloud.

There are two concepts here, let’s talk about ribonucleoside analogs first. Ribonucleosides are part of ribonucleic acid, and many ribonucleic acids are gathered together to form RNA.

RNA is part of the gene expression system in the human body, while the COVID-19 uses RNA directly as the genome.

As the name implies, ribonucleoside analogs refer to something that is very similar to ribonucleosides in chemical structure, and to be more blunt, it looks very similar to ribonucleosides.

But it looks like just a shape, not a real ribonucleoside. This can be used in drug development. As an RNA virus, ribonucleic acid is used as a raw material to construct a new RNA genome when COVID-19 replicates.

Ribonucleoside analogues look very similar and can replace the ribonucleic acid containing normal ribonucleosides in this process, but after the replacement, because it is a counterfeit, it cannot function normally, it blocks the path of virus replication. NS.

Based on this principle, many ribonucleoside analogs have been developed as antiviral drugs. Of course, the role of these drugs is not limited to antiviral. The upper level of ribonucleoside analogues is nucleoside analogues.

It includes not only molecules that can be mixed into RNA, but also molecules that can be mixed into DNA, covering everything from chemotherapy to anti-virus. Viruses and many other drugs.

Let’s talk about the prodrug. In theory, there is a ribonucleoside analogue that can mess up the replication of the new coronavirus with fakes. Is this definitely a medicine? uncertain. It is also necessary to consider how much medicine is needed to suppress the virus, and how much concentration this medicine can reach in the body after taking it.

If the drug is poorly absorbed by the human body, and the body cannot reach the required concentration at all (the antiviral drug needs to pass the intracellular concentration), it is useless.

Is this medicine cold? Not necessarily, a curve to save the country is to make some chemical modifications to the drug to make it a so-called “prodrug.” This prodrug itself may have a low ability to inhibit the virus, but it has very good characteristics in terms of absorption, and then can be metabolized into the active part of the body in the human body, so that it has the best of both worlds (Remdesivir also uses the former Drug design).

Molnupiravir is a prodrug. Its active ingredient was first screened out as an antiviral drug, code-named EIDD-1931. This active ingredient is the aforementioned ribonucleoside analogue. There are four codes for DNA, ATCG, and four AUCG for RNA. EIDD-1931 can pretend to be C or U in RNA.

When the new coronavirus replicates RNA, after EIDD-1931 takes the seat, the virus will see this as C for a while and U for a while. This is a bit like when we read a book with a typo after a few words, and in the end it becomes a celestial book that is hard to understand. If the virus’s own genes make up an astronomical book full of errors, it will naturally not survive.

But as mentioned before, if EIDD-1931 is directly made into medicine and eaten, the effective concentration cannot be achieved. So scientists synthesized Molnupiravir on the basis of EIDD-1931, but after entering the human body, EIDD-1931 will actually work.


How to consider the safety of the first oral drug of the COVID-19

Understand the structure and mechanism of Molnupiravir, then based on this information, how to explore the safety of this drug? First of all, the safety of Molnupiravir is not just a problem of Molnupiravir, the active ingredient EIDD-1931, which is finally formed in the body, must also be taken into consideration.

Secondly, as a nucleoside analog of EIDD-1931, it is necessary to consider the safety issues of this type of drug in the past research and development.

These two points also introduce the problem of mutagenicity. For a nucleoside analog, the possibility of causing mutations must be considered. Why? When a molecule can introduce mutations into the genome of a virus, it is natural to wonder if this ability is limited to the virus.

Human cells also have genomes, and then some cells have to divide and replicate, and there is also genome replication in the process. Therefore, whether a nucleoside analog will also interfere with the replication of the human genome must be considered.

Whether Molnupiravir is mutagenic or not should also be considered under whether EIDD-1931 is mutagenic. Especially according to the metabolism law of the drug, if it is completely metabolized into EIDD-1931 soon, then it needs to be clear, but it is the mutagenic risk of EIDD-1931.

The mutation risk of different nucleoside analogues is different because of the different mechanism. For example, HIV is a retrovirus, and its reverse transcriptase structure is very special. When researching nucleoside analog drugs against HIV, this structural peculiarity can be used to make drugs that are less risky to the human body and more harmful to HIV.

If the nucleoside analogues are poorly selective and have a high risk of human mutations, they may be more suitable for chemotherapeutics, because chemotherapeutics target cancer cells, which are human cells that divide frequently. These mutation risks can be studied by analyzing which cells are more sensitive according to the drug mechanism.

In fact, the mutagenic risk of Molnupiravir was proposed based on previous research on EIDD-1931. Since nucleoside analogues need to consider the risk of mutagenesis, scientists have also done related experiments when studying EIDD-1931.

There are many ways to assess the mutation risk of a drug. It can be roughly divided into two categories. One is in vitro experiments, which are mainly to see whether the drug can cause mutations in bacteria or cell lines during culture.

The other is animal experiments, which is to give mice and other experimental animals drugs to see if there are mutations in the animals. In the study of EIDD-1931, scientists found that adding this drug to cells cultured in vitro can trigger mutations. However, according to Merck’s statement, this phenomenon has not been observed in animal experiments.

In different experiments, some found that it can cause mutations, and some said no, then which one should I believe? In fact, it is not to say which one to believe, because it is very common for different methods of mutagenic research to be made differently. In practice, these different research methods are used, and then the possible risks are considered as a whole.

For example, it is observed in vitro cell culture, but not observed on animals. It is necessary to consider whether it means that the risk is relatively small, because the cell culture is updated quickly, that is, the number of divisions is large, and there are many opportunities to observe mutations. Of course, animals must also consider the actual concentration achieved in the body. Sometimes mice and humans, with the same drug, can reach different concentrations in the body, so it does not mean that animal experiments must be more convincing than cell experiments.

Judging from the current public information, it can only be said that the mutation risk of Molnupiravir needs to be studied. It cannot be said that it is completely risk-free, but it does not mean that it can cause mutations. However, it must be considered that Merck is already studying and will pay attention to it during the FDA review, so if it is finally passed, these possibilities must be taken into consideration.

A few months ago, a report on Science mentioned the controversy about the mutation risk of Molnupiravir. It was mentioned that a company previously considered whether EIDD-1931 could be used as a hepatitis C drug, but later gave up due to the possibility of mutation. This may worry many people.

In fact, deciding whether to continue research and development of a drug requires many considerations. If the same medicine is for different viruses, the dosage and course of treatment will be different, and the risk of side effects will be different.

Therefore, it is not a general statement that mutations may never become a safe drug. In fact, some of the nucleoside analogues have the possibility of mutation, and they are still very important antiviral drugs.

In addition, because a drug has a mutation risk, it does not mean that there is no other way to reduce the risk. Many cells in the human body do not divide. If you avoid minors and pregnant women, you can reduce the possible impact of this risk.

However, short-term medication is different from long-term medication. Molnupiravir is only used for 5 days to treat the COVID-19. There are still other antiviral drugs under development. If several drugs are used in combination, the dosage of a single drug may be reduced, and adverse reactions may be further controlled.


Conclusion: 

n people hear mutagenicity, it is easy to think of inducing cancer or causing neonatal deformities.

These two are indeed possible performances after mutagenesis. But that is a very extreme situation.

The assessment of mutagenicity of modern drugs is an assessment of the overall risk of causing mutations.

It is not said that there is a risk or that it will cause cancer or deformity. Discussing the mutagenic risk of Molnupiravir is only to say whether this drug has the possibility of causing human DNA mutations, and does not correspond to those extreme symptoms.

And the most important thing is that this risky pharmaceutical company and the FDA will carefully study, and the final approval, including the applicable population, will take all potential risks into consideration.

Reference:
Merck press release:
https://www.merck.com/news/merck-and-ridgebacks-investigational-oral-antiviral-molnupiravir-reduced-the-risk-of-hospitalization-or-death-by-approximately-50-percent-compared- to-placebo-for-patients-with-mild-or-moderat/

Mutation risk assessment method:

https://www.sciencedirect.com/science/article/abs/pii/S016635420000139X?via%3Dihub

How about the safety and mutagenicity of Merck oral COVID-19 drug?

(source:internet, reference only)


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