Earlier this February, the news that Gilead's drug remdesivir, which is under study, has cured patients with coronavirus spread across the country. In a short time, Remdesivir, an antiviral drug targeting Ebola, became “People's Hope”. Currently, Phase III clinical trials of Remdesivir in treating Coronavirus Disease 2019 (COVID-19) are still underway, which draw the wide attention of the public.
Recently, Emmie de Wit from the National Institutes of Health (NIH) published results in the journal PNAS, and found that in another non-human primate model of the coronavirus MERS-CoV infection, remdesivir could effectively prevent the virus infection and treat respiratory symptoms and lung damage caused by coronavirus. Despite the use of multiple “equals sign”, we have reason to believe that remdesivir will be the powerful, primary weapon against COVID-19.
Remdesivir is a nucleic acid prodrug with broad-spectrum antiviral activity, and is particularly effective against the deadly Ebola virus. In cell experiments, remdesivir can effectively inhibit the replication of multiple coronaviruses in human respiratory epithelial cells. In animal experiments, remdesivir can effectively treat MERS-CoV and SARS-CoV-induced respiratory syndrome in mice. Therefore, the pharmacodynamics of remdesivir in primates closer to humans has important clinical significance.
Researchers divided healthy macaques into three groups of six. The control group of macaques was injected with placebo, the preventive group was injected with 5 mg/kg of remdesivir 24 hours before MERS-CoV infection, and the treatment group was injected with 5 mg/kg of remdesivir 12 hours after viral infection, and then injected once daily. The researchers performed physical observation on all animals for 6 consecutive days, and then sacrificed to observe the lungs after 6 days. The experiment obtained the following results:
The researchers scored the appetite and fur status of the experimental animals. The higher the score is, the worse the status is. All patients in the control group experienced decreased appetite, fur folds, and respiratory disturbances; the remdesivir prevention group did not show any symptoms of respiratory diseases, and breathing was normal throughout the experiment; the respiratory rate of the treatment group increased, but was significantly lower than that of the control group. From the results of X-ray imaging, the lung infiltration of the animals in the remdesivir prevention and treatment group was significantly less than that in the control group.
The researchers used qRT-PCR to measure the viral nucleic acid content in the lung tissue of animals, and found that the viral lung load of the remdesivir prevention group was 2.5-4 log levels lower than that of the control group, and the viral lung load of the treatment group was also significantly lower than that of the control group, indicating that remdesivir effectively inhibited virus reproduction.
The remdesivir control group had normal lung tissues and no signs of viral infection. The treatment group (5/6) had macroscopic tissue lesions, but the total area was significantly smaller than the control group.
Therefore, pre-administration of remdesivir can completely inhibit the replication of MERS-CoV in the respiratory tract and significantly reduce the possibility of pneumonia infection. Since inpatient transmission accounts for one-third of MERS-CoV cases, prophylactic remdesivir treatment for patients, contacts, and health care workers at high risk for the virus can effectively reduce the number of pneumonia infections.
To date, few other drugs have been able to prevent MERS-CoV so thoroughly that almost no lung tissue lesions are observed. Remdesivir is comparable to hyperimmune plasma therapy and is currently one of the most promising drugs against primate coronavirus infection.
In addition, remdesivir has significant effects after viral infection. In this experiment, remdesivir was injected 12 hours after infection, but at this time it was close to the replication peak of MERS-CoV in Rhesus macaque. In theory, drugs that inhibit viral replication at this point have almost lost control of the virus. But remdesivir is an exception.
In many severe cases of MERS, viral RNA and living organisms can still be detected in respiratory samples a few weeks after the onset of symptoms, most likely due to the extension of the virus's replication time by the blessing of the underlying disease. Similarly, virus replication was observed to persist longer in immunocompromised Rhesus macaque. Therefore, remdesivir is not only beneficial for patients with early diagnosis of MERS, but also can improve the recovery of patients with severe MERS and underlying diseases.
Other possible treatment options for coronavirus pneumonia
Since the spread of COVID-19 is so fast, the drug development presents a priority. However, the research and development of new drugs is a time-consuming process, which requires huge input of money and effort. Several decades are needed from R & D to mass production. Therefore, to save time, the current clinical trials are based on certain clinical treatment effects or experimental results. In China alone, there are currently 32 clinical trials registered as “COVID-19 pneumonia”, involving drugs such as Fapilavir, Lopinavir/Ritonavir, Darunavir, and glucocorticoids, in addition to Remdesivir.
Anti-HIV drugs can block the enzymes needed for viral replication. During SARS, a small sample clinical trial found that lopinavir/ritonavir has a certain effect on the treatment of SARS. In addition, current in vitro research trials show that lopinavir/ritonavir can inhibit the replication of the Middle East Respiratory Syndrome Coronavirus (MERS-CoV) and Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) to exert antiviral activity effect.
The application of glucocorticoids in acute respiratory distress syndrome (ARDS) and severe viral pneumonia is still controversial as to whether it can reduce the mortality rate and improve the prognosis of patients. But more clinical trials are still needed.
In addition, China has initiated some trials to test the clinical effects of chloroquine. Chloroquine phosphate can effectively inhibit 2019-nCoV infection at the cellular level, and its role in the human body has yet to be clinically verified.
Traditional Chinese medicine has advantages such as low drug resistance and multi-target mechanism in the treatment of viral infections, so it has broad development prospects. Traditional Chinese medicine (TCM) has played an important role during SARS. In response to the epidemic, TCM experts provided different traditional Chinese medicine prescriptions and proprietary Chinese medicines choices for confirmed patients at different stages of the clinical treatment periods. Now, some TCM treatment has begun to show results.
Steps and stages of new drug development
The research on innovative drugs is a complex research system, which involves high-tech and interdisciplinary knowledge in chemistry, biology, and computational information science. The research process is mainly divided into two parts: new drug discovery and new drug development.
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