Can reduce 99% of the new crown virus load! Today's "Science" reports a new hope for fighting the epidemic

▎Editor of WuXi AppTec's content team When it comes to controlling the new crown epidemic, many people think of vaccines
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But if you want to return to life before the epidemic, vaccines are not the only answer: on the one hand, multiple vaccines all target the same target of the new coronavirus, and once the virus mutates, it will affect the effectiveness of the vaccine; on the other hand, the vaccine The key lies in the group vaccination rate, and it is still nowhere for the world to be vaccinated
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Today, "Science" magazine reported the progress of an innovative new crown therapy
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Since it is aimed at a conservative target for coronavirus infection and replication, it is expected to minimize the impact of mutations
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In a mouse model, it can reduce the virus titer in the lungs and nose by more than 200 times! In just 6 days, it can reduce the new coronavirus load by 99%
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What kind of magic drug is this? Let's start with its research and development process
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Previous research on key proteins of the sword finger found that after the new coronavirus enters the cells of the host, its viral genome produces about 30 different proteins, of which 16 proteins exist in the form of "polyproteins" and must be "cut".
In order to continue to exert its effect, the virus can continue to infect cells
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This process requires the participation of two proteases, which are called 3CLpro and PLpro
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It is conceivable that the enzyme responsible for "cutting off" the work is the key to the infection of the new coronavirus
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If this process can be inhibited, the replication process of the new coronavirus can be effectively inhibited
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What's more important for WuXi AppTec's content team's mapping is that the functions of these two proteases are "indispensable" to the life cycle of the virus, so they are unlikely to be like spike proteins that will mutate under the immune pressure brought by vaccines.
Further reduce the possibility of its resistance
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Based on these considerations, they have also become promising targets for potential new drugs
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In order to save time for drug development, the research team mentioned in the "Science" paper that they used the strategy of "old drugs and new use"-scientists first screened 1,900 drugs that are already in clinical use, looking for energy Drugs that inhibit common coronavirus infections
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▲A variety of old drugs have shown their ability to inhibit the new coronavirus (picture source: reference [1]) 108 kinds of drugs stand out from the crowd and are further used to test their ability to inhibit the new coronavirus
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In the end, they screened out 20 drugs that can also inhibit the replication of the new coronavirus, and the higher the drug concentration, the stronger the inhibition
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Subsequently, the researchers began to evaluate whether these 20 drugs would inhibit the key target of 3CLpro
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Only 8 kinds of molecules exhibit this characteristic, of which the strongest inhibitory ability is a molecule called masitinib
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What's more gratifying is that it can ignore the mutations in the S protein of the new crown variant virus-whether it is a wild-type new crown virus, or an Alpha, Beta, Gamma variant virus, it has shown a strong inhibitory ability
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▲Only 8 kinds of molecules can inhibit the key target 3CLpro, of which masitinib has the strongest inhibitory ability (picture source: reference [1]) What is sacred Masitinib? According to known information, it is a c-kit inhibitor that can be taken orally.
It has been approved to treat mast cell tumors in dogs.
It is also being evaluated in phase 2 and phase 3 clinical trials for its potential to treat a variety of human diseases
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The unique mechanism of action, the drug for the treatment of other diseases, can really inhibit the replication of the new coronavirus? In order to gain insights from the mechanism, the researchers further obtained the X-ray crystal structure of the combination of masitinib and 3CLpro
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Structural analysis shows that masitinib can bind between the two domains of 3CLpro in a non-covalent manner, blocking its key catalytic residues and active sites
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▲From the structural point of view, masitinib can block the key catalytic residues and active sites of 3CLpro (picture source: reference [1]) Considering the mechanism of action of masitinib, the researchers judged that it should be a competitive inhibitor
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To test this, this study also further evaluated the changes in the catalytic activity of 3CLpro with changes in substrate/inhibitor concentration
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As expected, masitinib showed classic competitive inhibition characteristics, and the inhibition constant Ki was only 2.
6 μM
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That is, at such a low concentration, half of the active site of the enzyme can be occupied
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We also mentioned above that the new coronavirus infection of cells requires the participation of two enzymes, 3CLpro and PLpro
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This study also evaluated the inhibitory effect of masitinib on PLpro and found that the molecule had no effect on it, indicating that the mechanism of action of masitinib is specific
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But for a variety of viruses with 3CLpro, masitinib can inhibit their replication, which also proves that it can target a broad spectrum of virus types
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Finally, the researchers decided to actually evaluate the anti-coronavirus effect of masitinib in animal models
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They used 20 mice expressing human ACE2 receptors and let them infect the new coronavirus through the nasal cavity
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After that, the mice were divided into two groups, one group received masitinib (25 mg/kg, twice a day), and the other group received PBS as a control
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▲Animal experiment results show that masitinib can reduce virus titer and improve lung pathology (picture source: reference [1]) On the sixth day of treatment, researchers began to analyze the treatment effect and found that masitinib significantly reduced the lungs of mice Virus titers in the lungs and nose, and improve the pathological conditions of the lungs
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The survival rate, weight loss, and clinical scores of mice also improved
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Taken together, the researchers pointed out that masitinib can reduce the viral load by more than 99% on the sixth day of treatment! At the end of the paper, the researchers concluded that masitinib exhibits a good viral inhibitory effect, and can reduce lung inflammation and enhance lung function
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In the future, we should evaluate the effect of this therapy in patients with new coronary disease
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From the point of view of the mechanism of action, the best therapeutic window of masitinib is in the early stage of infection, because it is expected to significantly inhibit the replication of the virus and control the disease in the first time
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The characteristics of oral administration also make it easier to use
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▲This research is expected to bring a new dawn to the control of the new crown epidemic (picture source: 123RF) “It takes a long time for the world to be vaccinated, and variant viruses that can produce immune escape also have the possibility of making the virus ineffective,” this research says One of the principals, Dr.
Nir Drayman of the University of Chicago said, “For this reason, there is a continuing need for innovative anti-viruses for the new coronavirus and new viruses that may emerge in the future
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It is very impressive to see the characteristics of masitinib in these two aspects .
Uplifting
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It can target all the new coronavirus variants we tested, including the highly contagious Alpha, Beta, and Gamma variants.
It also exhibits broad-spectrum antiviral activity and has the potential to treat many other viral diseases
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"Our data show that using masitinib in the early stages of infection can achieve the best results.
This is the time period when antiviral drugs are most effective," said Professor Savas Tay, another person in charge of this study, "because masitinib can be simple Oral administration, early treatment is a feasible strategy
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In the future, we need to study its potential benefits more carefully in clinical trials
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"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] AB Science announces the publication of an article in the world-renowned journal Science that confirms potential of masitinib as a treatment of Covid-19 with anti-viral activity against SARS-CoV-2 and all tested variants of concern, Retrieved July 20, 2021, from https: // Science-that-confirms-potential-of-masitinib-as-a-treatment-of-Covid-19-with-anti-viral-activity-ag.
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