Now that almost two years have passed since the start of the coronavirus disease 2019 (COVID-19) pandemic,1 the Korean government seems to be judging that the domestic pandemic has entered an adjustable range to some extent now. Starting in November 2021, the government is going to launch a policy - so-called ‘With-Corona’ - that it focuses all the capacity mainly on severe patients and relax regulatory policies such as social distancing. In fact, the term ‘With-Corona’ is a grammatically incorrect expression in English. However, the Korean government and media have already spread the word ‘With-Corona’ to the public to express the era of coexistence with the coronavirus, and the public has already accepted it as a routine term. Therefore, in this review, I will mainly use the term ‘With-Corona’ although it is close to a misnomer.

Many experts are concerned about this coexistence with COVID-19 policy. The first thing to consider is the fact that the current COVID-19 situation in Korea is not good. Since the summer of 2021, the number of confirmed cases, which had previously remained at around 1,000 per day, began to exceed 2,000 at the end of June. At the same time, the ratio of delta-variant also started to increase, and eventually, it accounted for nearly 100% of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) isolated from Korea as of October 2021.2

Another thing to consider is the vaccination completion rate. Since the COVID-19 vaccination campaign started in South Korea from the end of March 2021, as of October 25, the national vaccination rate has just exceeded 70%.3 Considering the current vaccination rate, it is expected that the minimum requirement of over 70% to 80% will be reached by November.4

It can be asserted that COVID-19 is unlikely to be completely eradicated.5 Experts believe the pandemic could end as soon as protection system for high-risk groups is complete. However, even after completion of high-risk group protection, a complete recovery to the good old days will not be easy. COVID-19 will continue to occur and re-emergence will repeat every year. After all, we have to live with the virus by getting a regular vaccine every year. This is almost similar to coexistence with influenza. However, one more puzzle is needed.

We can live with influenza because there are vaccines such as flu-shot as well as specific antiviral agents such as oseltamivir. Therefore, ‘With-Corona’ is possible only when antivirals that specifically act on SARS-CoV-2 are added as a final puzzle.

However, the pandemic is still with us and there is not enough time to develop brand new antivirals right now. Therefore, most of the antivirals being reviewed so far can only be repurposed drugs.

In this review, I will briefly summarize the available antivirals that are currently under development or coming soon, and consider which antiviral should be selected as the most appropriate piece of the puzzle for the realization of ‘With-Corona.’

Most of the antibiotics we use to attack bacteria exert a mechanism that directly destroys the bacteria themselves. So naturally, we tend to think that it would be ideal for antivirals to attack viruses directly as well. In fact, such an agent does exist. That is a disinfectant. However, the disinfectant is not a specific antiviral, and even harms human cells. Therefore, drugs that directly destroy and kill viruses cannot guarantee safety to humans. As such, the gap between the ideal antiviral and reality is very large. We have to target the other side of the virus. Thus, we examine the life cycle of the virus in detail and find the target there.67

SARS-CoV-2 initiates invasion into the host cell with attachment and entry, and then produces viral proteins therein and proceeds with replication. After that, it advances through assembly and packaging, goes out of the cell, finds a new host cell, and moves on to the next life cycle. In this series of processes, we can select several targets (Fig. 1).

In the development of antiviral, we also need to shift our paradigm of thinking. Antivirals do not necessarily attack only viruses, and even if we interfere with pathways in the host used by the virus, we can sufficiently suppress the virus. Therefore, drugs targeting the host protein used by SARS-CoV-2 are also being actively investigated. Viruses can resist virus-targeting antivirals by mutation, whereas host proteins do not betray us. These drugs also have the potential to become broad-spectrum antivirals. In this respect, host-targeting antiviral may be a more ideal treatment than virus-targeting antiviral. However, there is a concern about toxicity in that it acts on the host. As of 2021, as host-targeting antivirals, CTC-445.2d, an angiotensin converting enzyme 2 (ACE2) mimic, is investigated.26 As another entry-inhibitor, camostat and nafamostat, which inhibit transmembrane protease serine subtype 2 (TMPRSS2), are being studied.2728 In particular, camostat is an oral drug that is currently in clinical trial.29

Several antiparasitic agents were being considered for the treatment of COVID-19, but chloroquine and hydroxychloroquine were found to be ineffective.30 Ivermectin is also being considered for potential as a treatment for COVID-19.31 Artesunate/pyronaridine will be tested in the next phase of WHO solidarity trial.32

In the early days of the COVID-19 pandemic, remdesivir was expected as a specific treatment agent. The effect was also verified in Korea, and relatively encouraging results were obtained.33 Regrettably, in the WHO solidarity trial, remdesivir has reported to be little or no effect on 28-day mortality or the in-hospital course of COVID-19 among hospitalized patients. The disappointing results came out that there was no clinical benefit.30

Currently, the Korean government is announcing that it will purchase molnupiravir by the end of 2021.

In a recent study, it has been reported that molnupiravir had a superior viral clearance rate compared to placebo group and was generally well tolerated.34 As good results are coming out in the phase 2/3 clinical trial of molnupiravir that has been carried out so far, it is expected to be the most promising game changer as of October 2021.35

The most worrying aspect of the mechanism of this drug is that it is a mutation inducer. Of course, it is a drug that causes mutations in viruses and has little effect on human polymerase. However, as inferred from the case that nucleoside analogues used in anti-retroviral treatment are harmful to human mitochondrial DNA polymerase,36 molnupiravir may induce mutations in human DNA or RNA.37 Perhaps the risk will increase if this antiviral intervenes at a time when nucleoside replication in human cells is active. A typical example is pregnancy. Therefore, administration of this drug to pregnant women or children should be carefully considered.

The treatment agent for ‘With-Corona’ should satisfy the following conditions. First, it must be a drug that can be taken by mouth. Second, non-hospitalized patients with mild to moderate symptoms should be targeted. Finally, it should not be expensive. Among the above three conditions, molnupiravir currently satisfies the first two. However, the problem is that it is still expensive.

But we are optimistic that the price will be eventually adjusted to a reasonable level if demand for the drug grows. And this is an issue that should be dealt with as a concept of welfare at the government level. Fortunately, the South Korean government says it will pay for the drug for patients for the time being.38

Of course, no one knows yet whether molnupiravir will succeed in ending the COVID-19 pandemic. Unfortunately, if molnupiravir fails, we should hope for other RdRp inhibitors such as AT-527 or PIs, and so on. If specific antiviral is added to achieving herd immunity through vaccination, can we get out of the yoke of the COVID-19 pandemic? I expect that is possible, although COVID-19 will not completely disappear from the planet and will continue to accompany us as a seasonal cold. We are still living in an age of uncertainty, but I think we are wisely overcoming hardships with the power of rational thinking and science.