The antiviral principle of Merck's Molnupiravir, how safe and mutagenic is it?

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 stage of infection
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According to analysis, oral drugs are an important supplement to existing treatment methods, but they cannot replace vaccines
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However, the mutagenicity mentioned in the safety of the drug may cause many people to worry after reading
.

This article will focus on analyzing the antiviral principles of Molnupiravir, and then based on these principles, how to treat the safety of the drug, especially the risk of mutation
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Structure and mechanism of new coronavirus oral drugs

Considering the safety of drugs is inseparable from the analysis of the chemical structure and mechanism of action of the drugs
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From the structural point of view, Molnupiravir is a prodrug of ribonucleoside analogues
.

There are two concepts here, let's talk about ribonucleoside analogs first
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RNA is part of the human gene expression system, and the new coronavirus directly uses RNA as its genome
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As the name implies, a ribonucleoside analog refers to something that is very similar in chemical structure to a ribonucleoside.
More bluntly, it looks very similar to a ribonucleoside
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But it looks just a shape, not a real ribonucleoside
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Ribonucleoside analogues look very similar.
In this process, the ribonucleic acid containing normal ribonucleosides can be replaced, but after the replacement, because it is a counterfeit, it does not work properly, and it blocks the path of virus replication
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Based on this principle, many ribonucleoside analogs have been developed as antiviral drugs
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It includes not only molecules that can be mixed into RNA, but also molecules that can be mixed into DNA, including everything from chemotherapy to antiviral
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Let's talk about prodrugs
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If the drug is poorly absorbed by the body and the body simply cannot reach the required concentration (antiviral drugs need to pass through the intracellular concentration), then it is useless
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Is this medicine cold? Not necessarily.
The way to save the country by curve is to make some chemical modifications to the drug to make it a so-called "prodrug"
.

Molnupiravir is a prodrug
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When the new coronavirus replicates RNA, after EIDD-1931 takes the position, the virus will regard it as C for a period of time and U for a period of time
.
It's a bit like we read a book, after a few words, there is a spelling error, and in the end it becomes a very difficult to understand celestial book
.
If the virus's own genes constitute a astronomical book full of errors, it will naturally not survive
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But as mentioned earlier, if EIDD-1931 is directly made into medicine and eaten, effective concentration cannot be achieved
.
Therefore, scientists synthesized Molnupiravir on the basis of EIDD-1931, but after entering the human body, EIDD-1931 will really work
.

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

After understanding the structure and mechanism of Molnupiravir, how to explore the safety of the drug based on this? First of all, the safety of Molnupiravir is not only a problem of Molnupiravir, the final active ingredient EIDD-1931 formed in the body must also be considered
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Secondly, as a nucleoside analog of EIDD-1931, it is necessary to consider the safety of this type of drug in the past research and development
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These two points also lead to the problem of mutagenicity
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For nucleoside analogs, the possibility of causing mutations must be considered
.
Why? When a molecule can mutate the viral genome, people naturally wonder whether this ability is limited to the virus
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Human cells also have a genome, and then some cells have to divide and replicate.
In this process, there is also genome replication
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Therefore, whether nucleoside analogs will also interfere with the replication of the human genome must be considered
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Whether Molnupiravir is mutagenic should also be considered based on whether EIDD-1931 is mutagenic
.
Especially according to the metabolism of the drug, if it is completely metabolized into EIDD-1931 soon, then it needs to be clear, but this is the mutagenic risk of EIDD-1931
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The risk of variation of different nucleoside analogues is different due to different mechanisms
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For example, HIV is a retrovirus, and its reverse transcriptase structure is very special
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When studying anti-HIV nucleoside drugs, this structural feature can be used to make drugs that are less risky to the human body and more harmful to HIV
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If nucleoside analogs are less selective and have a higher risk of human mutations, then they may be more suitable for chemotherapy because chemotherapy targets cancer cells, which are human cells that divide frequently
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The risk of these mutations can be studied by analyzing which cells are more sensitive according to the mechanism of the drug
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In fact, the mutagenic risk of Molnupiravir is based on previous research on EIDD-1931
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Because nucleoside analogs need to consider the risk of mutations, scientists also did related experiments when studying EIDD-1931
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There are many ways to assess the risk of drug mutation
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It can be roughly divided into two categories
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One is in vitro experiments, mainly to observe whether the drug can cause mutations in bacteria or cell lines during the culture process
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The other is animal experiments, in which mice and other experimental animals are given drugs to see if the animals have mutations
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In the study of EIDD-1931, scientists found that adding this drug to cells cultured in vitro can trigger mutations
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However, according to Merck’s statement, this phenomenon has not been observed in animal experiments
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In different experiments, some people found that it would cause mutations, and some people said no, so which one should I believe? In fact, this is not to say which one should be trusted, because different mutagenesis research methods are different.
Very common
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In practice, use these different research methods, and then consider the possible risks as a whole
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For example, it can be observed in cell cultures in vitro, but not in animals
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It is necessary to consider whether this 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
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Of course, the animal must also consider the actual concentration achieved in the body
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Sometimes rats and humans take the same drug and can reach different concentrations in the body, so it does not mean that animal experiments must be more convincing than cell experiments
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From the current public information, it can only be said that the mutation risk of Molnupiravir needs to be studied
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It cannot be said that it is completely risk-free, but that does not mean that it will cause mutations
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However, it must be considered that Merck in the United States is already studying and will pay attention during the FDA review, so if it is finally passed, these possibilities must be considered
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A few months ago, a report in "Science" magazine mentioned the controversy about the risk of Molnupiravir mutations
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It was mentioned that a company had previously considered whether EIDD-1931 could be used as a hepatitis C drug, but then abandoned it due to the possibility of mutation
.
This may worry many people
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In fact, there are many factors to consider when deciding whether to continue research and development of a drug
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If the same drug treats different viruses, the dosage and course of treatment will be different, and the risk of side effects will also be different
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Therefore, mutation may never become a safe drug, which is not a general statement
.
In fact, some nucleoside analogues have the possibility of mutation, and they are still very important antiviral drugs
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In addition, because a drug has a mutation risk, this does not mean that there is no other way to reduce the risk
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Many cells in the human body cannot divide
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If you avoid minors and pregnant women, you can reduce the possible effects of this risk
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However, short-term medication is different from long-term medication
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Molnupiravir is only used to treat COVID-19 for 5 days
.
There are still other antiviral drugs under development
.
Combination of multiple drugs can reduce the dosage of single drugs and further control adverse reactions
.
 

in conclusion:

When many people hear of mutagenicity, they tend to think of inducing cancer or causing neonatal deformities
.

These two are indeed possible manifestations after mutation
.
But this is a very extreme situation
.

The mutagenicity assessment of modern drugs is an assessment of the overall risk of causing mutations
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It's not that it has the risk of causing cancer or teratogenicity
.
Discussing the mutagenic risk of Molnupiravir is only to say whether this drug may cause human DNA mutations, which does not meet these extreme symptoms
.

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 into account all potential risks
.

 Refer to Merck's press release :
https:// approximately-50-percent-compared- to-placebo-for-patients-with-mild-or-moderat/

Mutation risk assessment method:

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