Just now, the world's first oral anti-coronavirus drug was approved

Just now, the anti-new crown virus drug Molnupiravir (EIDD-2801/MK-4482) has been approved by the British Medicines and Healthcare Products Regulatory Agency (MHRA) for the treatment of patients with mild to moderate new coronary pneumonia
.

This means that mankind finally has the first oral drug to fight the new coronavirus
.

The UK MHRA's approval is based on the interim analysis results of the Phase 3 clinical trial (MOVe-OUT)
.

From the results of the study, among high-risk patients with mild to moderate new coronary pneumonia who do not need to be hospitalized (at least one risk factor in the body indicates that they may develop critical illness), compared with the control group, oral Molnupiravir will hospitalize the patients or The risk of death is reduced by about 50%, and the risk of death is reduced by 100% [1]
.

Due to the excellent trial data, the recruitment for this study was terminated early after consultation with the US FDA
.

The chemical formula of Molnupiravir is estimated to be unknown to many people, and the cumulative number of confirmed cases of new coronary pneumonia worldwide has exceeded 200 million
.

The birth of the new crown vaccine has curbed the global spread of new crown pneumonia to a certain extent, preventing countless people from contracting the new crown virus and dying due to infection
.

However, the development of anti-coronavirus drugs has been lagging behind
.

To this day, the only anti-new coronavirus drug approved by the US FDA for marketing is Remdesivir, which is used to treat patients with severely ill hospitalized patients with new coronavirus infection
.

However, the efficacy of Radixivir is limited.
The final results of the Phase 3 clinical study ACTT-1 showed that the median recovery time of patients receiving Radixivir was shortened by 5 days [2]
.

It is worth mentioning that on day 29, patients who required low flux oxygen at baseline benefited more.
The mortality rate was 13% in the placebo group and 4% in the remdesivir group (HR, 0.
30) [2]
.

Many researchers believe that to deal with the new coronavirus, we must "start early and start hard
.
"
Because as the patient's condition gets worse, the treatment becomes more difficult, and the efficacy of the drug becomes worse
.

Therefore, it is particularly important to develop effective, inexpensive and accessible drugs for early infections
.

In fact, in the early days of the new crown epidemic, scientists were constantly screening for any drugs that might fight the new crown virus
.

The new coronavirus Molnupiravir is the product of scientists' efforts
.

Molnupiravir was originally developed by Drug Innovations at Emory (DRIVE), a non-profit biotechnology company wholly-owned by Emory University, to treat Venezuelan equine encephalitis virus infections transmitted by mosquitoes
.

In 2015, DRIVE CEO George Painter provided Molnupiravir to Mark Denison, a virologist at Vanderbilt University, to test the effectiveness of Molnupiravir against coronavirus
.

As a result, Molnupiravir performed well, and it has a strong inhibitory effect on various coronaviruses such as SARS and MERS [3]
.

After the outbreak of the new crown epidemic, DRIVE licensed Molnupiravir to the pharmaceutical company Ridgeback Biotherapeutics, which was jointly developed by Ridgeback Biotherapeutics and Merck
.

Just last year, researchers' studies on ferrets showed that Molnupiravir can not only inhibit the replication ability of the new coronavirus, but also inhibit the spread of the virus from infected ferrets to uninfected ferrets[4]
.

The Phase 3 clinical trial MOVe-OUT, which was launched almost in the same period, also released the aforementioned interim analysis data on October 1 this year
.

Specifically, after 29 days of treatment, 7.
3% of the patients in the Molnupiravir group were hospitalized (28/385), and no patients died; while 14.
1% of the patients in the placebo group were hospitalized or died (53/377), of which 8 patients Name died [1]
.

What's even more powerful is that from the analysis results, Molnupiravir has shown a consistent effect on the new crown variants such as the Delta variant, the Gamma variant and the Mu variant
.

In terms of the incidence of adverse events, the incidence of any adverse events in the Molnupiravir group and the placebo group were 35% and 40%, respectively, the proportions of drug-related adverse events were 12% and 11%, and the proportion of discontinuation of treatment due to adverse events They are 1.
3% and 3.
4% respectively [1]
.

In general, Molnupiravir is safe and effective for high-risk patients with mild to moderate new coronary pneumonia who do not need to be hospitalized
.

The life cycle of the new coronavirus, Molnupiravir, like Redecive, is a nucleotide analogue
.

Therefore, they all have the opportunity to insert into the RNA of the new coronavirus
.

Although they are the same class of drugs, the antiviral mechanisms of Molnupiravir and Remdesivir are not the same
.

Previous studies have shown that Remdesivir mainly competes with ATP [5]
.

That is to say, in the process of RNA synthesis, RNA-dependent RNA polymerase (RdRp) will add radcivir where ATP should have been added, and radcivir will be directly stuck between RdRp and template RNA, resulting in The synthesis of RNA ends, and the replication of the virus ends
.

Simply put, the new crown virus was "stuck" by Redcivir
.

The action stage of nucleotide analog prodrugs is different from that of Molnupiravir, and its mechanism of action is at least two different from that of Remdesivir
.

The first difference is that the structure of Molnupiravir is very flexible.
It can not only simulate CTP, but also UTP, which means that Molnupiravir will compete with CTP and UTP at the same time and randomly insert into the RNA of the new coronavirus [6, 7]
.

Although Molnupiravir will also be inserted into the RNA of the new coronavirus, Molnupiravir will not "stuck" RdRp, but let RdRp complete the synthesis of the new coronavirus RNA [6, 7]
.

This is the second difference
.

At first glance, Molnupiravir seems to have failed to inhibit the replication of the new coronavirus
.

In fact, the foreshadowing of the collapse of the new crown virus has been laid
.

You know, no matter where Molnupiravir is inserted into the RNA, it is a point mutation
.

When Molnupiravir was inserted enough, the new crown virus collapsed and died
.

For this antiviral mechanism, researchers call it "lethal mutagenesis
.
"
The process of fatal mutagenesis is worth mentioning.
Because the mutations caused by Molnupiravir are random, it is difficult for the new coronavirus to develop resistance to this antiviral method.
Preclinical basic research has also confirmed this [6, 7]
.

This "fatal mutagenesis" antiviral method also makes some researchers worry that it will affect DNA synthesis and bring some safety problems
.

As there is no relevant safety data released, we are not sure whether this concern is necessary
.

However, Daria Hazuda, Merck’s chief scientific officer, believes that the drug is safe as long as the drug is administered as planned
.

Matching after insertion So is it possible for Molnupiravir to curb the development of the new crown epidemic? In the view of researchers, there are at least two key issues to be solved [8]
.

First, from the current research data, people infected with the new crown need to use Molnupiravir in the early stages of infection, which is very challenging for many countries with insufficient diagnostic capabilities
.

Second, the price of Molnupiravir is not cheap
.

It is understood that the US government has agreed to purchase 1.
7 million courses of Molnupiravir at a price of 1.
2 billion U.
S.
dollars.
In this way, the cost of a course of treatment exceeds 700 U.
S.
dollars
.

Although it is much cheaper than Remdesivir and antibodies, the price is still too expensive for most countries
.

Fortunately, pharmaceutical companies are seeking solutions
.

In general, even if specific anti-coronavirus drugs really appear, it still depends on the cooperation of all countries around the world.
Only when early diagnosis and treatment is achieved globally can the spread of the new crown virus be truly curbed
.

After all, in the face of a global epidemic, mankind is a community with a shared future
.

References: [1].
https:// -50-percent-compared-to-placebo-for-patients-with-mild-or-moderat/[2].
Beigel JH, Tomashek KM, Dodd LE, et al.
Remdesivir for the Treatment of Covid-19-Final Report .
N Engl J Med.
2020;383(19):1813-1826.
doi:10.
1056/NEJMoa2007764[3].
Sheahan TP, Sims AC, Zhou S, et al.
An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV- 2 in human airway epithelial cell cultures and multiple coronaviruses in mice.
Sci Transl Med.
2020;12(541):eabb5883.
doi:10.
1126/scitranslmed.
abb5883[4].
Cox RM, Wolf JD, Plemper RK.
Therapeutically administered ribonucleoside analogue MK-4482/EIDD-2801 blocks SARS-CoV-2 transmission in ferrets.
Nat Microbiol.
2021;6(1):11-18.
doi:10.
1038/s41564-020-00835-2[5].
Tchesnokov EP, Feng JY, Porter DP, Götte M.
Mechanism of Inhibition of Ebola Virus RNA-Dependent RNA Polymerase by Remdesivir.
Viruses.
2019;11(4):326.
Published 2019 Apr 4.
doi:10.
3390/v11040326[6].
Urakova N, Kuznetsova V, Crossman DK, et al.
β-d-N4-Hydroxycytidine Is a Potent Anti-alphavirus Compound That Induces a High Level of Mutations in the Viral Genome.
J Virol.
2018;92(3):e01965-17.
Published 2018 Jan 17.
doi:10.
1128/JVI.
01965-17[7].
Kabinger F, Stiller C, Schmitzová J, et al.
Mechanism of molnupiravir- induced SARS-CoV-2 mutagenesis.
Nat Struct Mol Biol.
2021;28(9):740-746.
doi:10.
1038/s41594-021-00651-0[8].
https:// /d41586-021-02783-1 The author of this articleBioTalkerViruses.
2019;11(4):326.
Published 2019 Apr 4.
doi:10.
3390/v11040326[6].
Urakova N, Kuznetsova V, Crossman DK, et al.
β-d-N4-Hydroxycytidine Is a Potent Anti-alphavirus Compound That Induces a High Level of Mutations in the Viral Genome.
J Virol.
2018;92(3):e01965-17.
Published 2018 Jan 17.
doi:10.
1128/JVI.
01965-17[7].
Kabinger F, Stiller C , Schmitzová J, et al.
Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis.
Nat Struct Mol Biol.
2021;28(9):740-746.
doi:10.
1038/s41594-021-00651-0[8].
https:// Author of this articleBioTalkerViruses.
2019;11(4):326.
Published 2019 Apr 4.
doi:10.
3390/v11040326[6].
Urakova N, Kuznetsova V, Crossman DK, et al.
β-d-N4-Hydroxycytidine Is a Potent Anti-alphavirus Compound That Induces a High Level of Mutations in the Viral Genome.
J Virol.
2018;92(3):e01965-17.
Published 2018 Jan 17.
doi:10.
1128/JVI.
01965-17[7].
Kabinger F, Stiller C , Schmitzová J, et al.
Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis.
Nat Struct Mol Biol.
2021;28(9):740-746.
doi:10.
1038/s41594-021-00651-0[8].
https:// Author of this articleBioTalkerPublished 2018 Jan 17.
doi:10.
1128/JVI.
01965-17[7].
Kabinger F, Stiller C, Schmitzová J, et al.
Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis.
Nat Struct Mol Biol.
2021;28 (9):740-746.
doi:10.
1038/s41594-021-00651-0[8].
https:// Author of this articleBioTalkerPublished 2018 Jan 17.
doi:10.
1128/JVI.
01965-17[7].
Kabinger F, Stiller C, Schmitzová J, et al.
Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis.
Nat Struct Mol Biol.
2021;28 (9):740-746.
doi:10.
1038/s41594-021-00651-0[8].
https:// Author of this articleBioTalker