New Progress of Potential "Specific Drugs" for COVID-19: Masitinib + S2H97

Since the outbreak of COVID-19 at the end of 2019, it has spread all over the world. Up to now, more than 190 million confirmed cases of COVID-19 have been reported worldwide, and more than 4.11 million patients have died, causing great disasters to all mankind. 

For COVID-19, besides speeding up vaccination, it is also very urgent to find a safer and more effective treatment plan. Looking back on the history of influenza in the past century (1918-2020), the real way to protect human society from the impact of influenza is the combination of "influenza vaccine + oral special drugs" -- "prevention and treatment", especially the emergence of oral anti-influenza drugs (oseltamivir, etc.), which enables people to keep normal social activities after being infected with influenza virus by taking their own medicines and simple protection. 

For the prevention and treatment of COVID-19, "COVID-19 vaccine + oral anti-COVID-19 drugs" is also a better choice, which is more convenient and lower in social cost. At present, there are many small molecule antiviral candidate drugs in the clinical research stage in the world. Recently, two more drugs and medical supplies products have made new progress, which brings hope for the victory of fighting against the pandemic. 

New use of the existing medicine - masitinib 

Masitinib is an oral tyrosine kinase inhibitor, which can competitively inhibit the activity of the main protease 3CLpro in SARS-CoV-2, thus inhibiting the replication of SARS-CoV-2. 

Vivo experiments in mice showed that masitinib could reduce the SARS-CoV-2 titers in the lungs and noses of mice to less than 1% within 6 days, and relatively mitigate lung inflammation. In addition, masitinib is also effective against COVID-19 α, β and γ mutant strains in vitro.    

In this research on masitinib, scientists used the strategy of "new use of the existing medicine" - they first screened 1,900 drugs that have been used in clinic to find drugs that can inhibit common coronavirus infection. 

108 drugs stood out and were further used to test their inhibitory ability against SARS-CoV-2. At last, the researchers began to evaluate whether the 20 selected drugs could inhibit the key target of 3CLpro, among which the strongest one was a molecule called masitinib. 

Researchers actually evaluated the anti-COVID-19 effect of masitinib in animal models. They used 20 mice expressing human ACE2 receptor to infect SARS-CoV-2 through nasal cavity. After that, these mice were divided into two groups, one received masitinib (25mg/kg, twice a day) and the other received placebo as control. 

On the sixth day of treatment, the researchers began to analyze the treatment effect, and found that masitinib significantly reduced the virus titers in the lungs and noses of mice, and improved the pathological conditions of the lungs. The survival rate, weight loss and clinical score of mice also improved. 

On the whole, the researchers pointed out that masitinib could reduce viral load by more than 99% on the sixth day of treatment. At the end of the paper, the researchers pointed out that masitinib was effective to inhibit the virus, and could reduce lung inflammation and enhance lung function. The effect of this therapy in patients with COVID-19 should be evaluated. From the effect of masitinib, its best therapy window is in the early stage of infection, because it is expected to significantly inhibit the replication of virus and control the disease at the first time. The characteristics of oral administration also make it easier to apply. 

In addition, masitinib can be used as a broad-spectrum antiviral drug. Because it not only can effectively inhibit SARS-CoV-2 and its mutants, but also is effective against a variety of coronaviruses and small RNA viruses, and has the potential to treat other viral infections. 

Broad-spectrum neutralizing antibody-S2H97 

Neutralizing antibody against SARS-CoV-2 is one of the important means to treat and prevent COVID-19. However, with the emergence of various SARS-CoV-2 mutant viruses, the neutralizing efficacy of some neutralizing antibodies has decreased significantly. It is urgent and important for researchers to figure out how to cope with the continuous evolution of SARS-CoV-2 and develop neutralizing antibody or COVID-19 vaccine with "broad-spectrum effect" and avoid virus escape.       

Recently, researchers discovered a broad-spectrum neutralizing antibody named S2H97, which keeps neutralizing activity against various strains of Sarbe coronavirus subgenus. SARS virus and MERS virus, which cause diseases in human beings, belong to Sarbe coronavirus subgenus. 

In the challenge experiment in hamsters, S2H97 was injected into animals in advance, which can reduce the number of viral RNA copies by more than 10,000 times compared with the control animals. Finally, the researchers examined whether the sera of patients infected with SARS-CoV-2 or inoculators of COVID-19 vaccines contained antibodies with the same binding site as S2H97. They found that there were very few antibodies in serum that competed with S2H97 for binding to the same site. The researchers pointed out in the paper that this may be because the epitope bound by S2H97 is not easily accessible, and the ability to trigger immune system response is not strong. However, in view of the broad-spectrum neutralizing effect of S2H97, the immune antigen designed based on RBD (receptor binding domain) of spike protein can expose this epitope, thus more effectively stimulating neutralizing antibody similar to S2H97. 

Based on the detection of antibody neutralization capacity, more conservative epitopes may be found, which is helpful for the development of antibodies or vaccines with stronger immune escape resistance and can cope with novel coronaviruses that may appear in the future. 

COVID-19 has become a global pandemic, which has caused great damage to the global economy and people's lives and health. Researchers are also rapidly carrying out various studies. Virologists have further revealed the structure and function of various proteins in SARS-CoV-2. Since the outbreak of COVID-19, more and more experts have recognized that "vaccine prevention + drug treatment" is the best combination of medical intervention in the prevention and treatment of COVID-19. However, compared with the introduction of vaccines one after another, there is no "special drug" in the market that can really treat COVID-19. Despite the challenges, dawn is just around the corner. 

Reference: 

1. Nir Drayman et al., (2021), Masitinib is a broad coronavirus 3CL inhibitor that blocks replication of SARS-CoV-2, Science, DOI: 10.1126/science.abg5827；

2. Starr et al., (2021). SARS-CoV-2 RBD antibodies that maximize breadth and resistance to escape. Nature, https://doi.org/10.1038/s41586-021-03807-6.