After Remdesivir, where is the next hope?

The COVID-19 is a problem that we will not be able to escape from 2020 to the present, and even many years to come.

At present, a number of COVID-19 vaccines have been approved for the market worldwide, and many countries are advancing their vaccination plans in an orderly manner. However, only one anti-coronavirus treatment drug is officially approved.

Throughout the past few decades, starting from the first approved antiviral drug idoxuridine in 1963, chronic infections caused by HIV, hepatitis B virus, and hepatitis C virus have all been approved for related drugs, but humans The development of antiviral drugs is still very slow.

What restricts the development of antiviral drugs? This starts with the unique mechanism of antiviral drugs.

Mechanism of action of antiviral drugs

The virus has a very simplified structure. After invading the host cell, the virus will "cheat" the cell to complete gene replication and capsid protein production. After assembly, the new virus will escape from the cell and infect new targets.

Every step of the virus life cycle, including entry into living cells, biosynthesis, assembly and release, its proteins or genes need to interact with host molecules. Antiviral drugs use this process to interfere by mimicking host molecules. The life cycle of the virus, thereby reducing the spread of the virus.

However, antiviral drugs cannot directly destroy the virus, so the human immune system is required to remove the virus to a certain extent. Therefore, when the number of viruses is very low, antiviral treatment can be started as soon as possible to maximize the effect of antiviral drugs.

Difficulties in the development of antiviral drugs

There are several difficulties in the development of antiviral drugs, which limit the development of antiviral drugs.

First of all, an ideal antiviral drug needs to stop the virus while not destroying the normal function of healthy cells. The survival and metabolism of viruses depend on host cells, so they cannot provide diversified targets by themselves. Unlike antibiotics, antibiotics can act on the unique cell walls of bacteria.

Secondly, there are very few natural antiviral drugs, so most antiviral drugs require scientists to create from scratch. In addition, the shape of antiviral drugs may be limited by their functions. If drugs want to interfere with virus replication, sometimes they need unique shape adaptations.

Although the development conditions are harsh, the importance of antiviral drugs cannot be replaced. For example, hepatitis C can become a curable chronic disease, thanks to the efficacy of antiviral drugs.

Antiviral drugs on the COVID-19 battlefield

In the past year, the highly anticipated Remdesivir has experienced its ups and downs.

Remdesivir is a nucleotide analog that can replace adenine nucleotides to participate in the synthesis of RNA strands and inhibit RNA-dependent RNA polymerase (RdRp), which hinders the massive replication of viruses.

On January 31, 2020, the "New England Journal of Medicine" reported that the first confirmed case of the new coronavirus in the United States received an intravenous infusion of Redcivir on the 7th day of hospitalization. His symptoms improved rapidly and oxygen saturation was restored. It's 94%~96%.

For a time, Remdesivir was regarded as "the hope of the people". It was not yet on the market. It was not only approved as a sympathetic medicine, but also received emergency authorization.

However, the clinical performance of remdesivir was not very satisfactory. In the end, the WHO issued a document based on data from multiple trials in November 2020: “There is no evidence to prove that remdesivir can improve the survival rate of new crown patients. It is not recommended to Used by hospitalized patients".

A Redcivir has temporarily "fallen down". In the new crown battlefield, what other antiviral drugs are about to stand up?

One of the most promising drugs at present is molnupiravir (EIDD-2801/MK-4482) developed by Merck and Ridgeback Biotherapeutics.

At the CROI 2021 meeting on March 10, Merck and Ridgeback reported the results of the clinical phase IIa trial of molnupiravir.

In 202 patients who developed COVID-19 symptoms within 7 days, after taking molnupiravir for 5 days, the positive rate of infectious virus isolation and culture in nasopharyngeal swabs was 0% (0/47), compared with 24% of patients in the placebo group (6 /25). Moreover, the drug is safe, and none of the four serious adverse events reported is considered to be related to the study drug.

Unlike remdesivir, molnupiravir is an oral antiviral drug. As a prodrug of the nucleoside analogue N4-hydroxycytidine (NHC), it has broad-spectrum antiviral activity against a variety of viruses, including MERS -CoV and SARS-CoV-2, previously it was also regarded as "Oral Remdesivir similar drugs."

Although the announcement of the clinical results was not as good as Redcivir's impact at the time, the hope of molnupiravir is self-evident.

Gilead is currently developing a remdesivir inhalation preparation, and Roche also has a number of anti-coronavirus drugs under development. See the table below for details.

We don't know when the next global epidemic like the new crown will come, but now we have many vaccines and anti-coronavirus drugs under development. In the COVID-19 pandemic, the scientific researchers who succeeded in bringing us the rapid development and approval of vaccines, the future direction of science is the direction of eliminating the COVID-19 epidemic.