Today, a leading academic journal, Cell, published an online paper on the new coronavirus, revealing the key proteins needed for the new coronavirus to invade cells, and pointing out that a clinically proven protease inhibitor has shown inhibition in cell experiments and is expected to be a potential treatment.
It is worth noting that although this article has been peer-reviewed and accepted by Cell, the final proofreading has not yet been completed, so there may be some details in the article. Cell said the article was published in advance in order to get more people to see the information as early as possible. Click on “Read the original/Read more” at the end of the article to access the online version of the paper.
Let’s put it right. Since the outbreak of the new coronary virus, scientists have done a lot of research, but also revealed the new coronavirus in the sequence of the similarity to SARS virus. As a result, some scientists have speculated that the similarities in these sequences may represent a similar process by which the two coronaviruses invade cells.
Specifically, the S protein of the coronavirus is the “siege hammer” of invading cells. In this, the S1 subunit binds to the receptors on the cell surface, allowing the virus to connect to the cell. At the same time, under the action of protease, specific sites of the S protein are cut open to promote the fusion of the virus envelope with the cell membrane, thus allowing the virus to enter the cell.
From past experience, the SARS virus binds to ACE2 receptors on the cell surface, and the invading cells also require a protease called TMPRSS2. Given the similarity between the new coronavirus and the SARS virus sequence, many people also speculate that the new coronavirus is using the same ACE2 receptor. In fact, recent studies have provided substantial evidence to support this claim, such as the high affinity between the S protein of the new coronavirus and the ACE2 receptor, and the structure of the frozen electron scopies that bind struck.
Related: Science Today: Scientists reveal high-definition structure of the new coronavirus S protein, promising to help develop vaccine and diagnostic technologies (Photo: Jason McLellan/Univ). Of Texas at Austin
So is the new coronavirus and SARS virus using the same receptors to invade cells? The researchers first did a quick experiment to infect a range of cells with both viruses. The results showed that the two viruses were almost identical in the cell types that could infect them, suggesting that they may have used similar cell receptors. Subsequent sequence pairs also found that several key amino acids combined with ACE2 receptors were also conservatively present in the new coronavirus. Other coronaviruses that do not bind to ACE2, whose receptors bind to the key amino acids in the domain, do not appear in the new coronavirus. These results also support the idea that the new coronavirus binds to ACE2 receptors.
Next, it’s a key experiment. The researchers used a special cell line called BHK-21. Typically, it is insensitive to SARS viruses and new coronaviruses, which are not effective in invading BHK-21 cells. The scientists then expressed ACE2 receptors, DPP4 receptors (receptors used by MERS viruses), and APN (another non-severe coronavirus binding receptor) in BHK-21 cells. The results showed that the new coronavirus and SARS virus could effectively invade BHK-21 cells only if the ACE2 receptor was expressed. In addition, the serum that inhibits ACE2 also inhibits the invasion of BHK-21 cells by the new coronavirus and SARS virus. These results strongly suggest that the ACE2 receptor is the binding receptor required for the new coronavirus to invade cells.
The new coronavirus and SARS virus can only invade these cells after the ACE2 receptor is expressed (Photo: Resources 1)
The next question for the researchers is whether the new coronavirus, like the SARS virus, uses a similar protease to cut the S protein and invade the cells. For SARS viruses, catB/L and TMPRSS2 both can help with virus invasion, which is even more critical.
In the study, the scientists used a special cell line that did not express TMPRSS2 to assess the role of CatB/L individually. They found that when catB/L activity was inhibited, both the new coronavirus and the SARS virus lost the ability to invade cells, suggesting that CatB/L, a protease, also played a role in the new coronavirus invading cells.
On the other hand, the researchers also assessed the role of TMPRSS2, a protease. They found that a protease inhibitor called camostat mesylate effectively inhibited the activity of TMPRSS2 and partially inhibited the invasion of cells by the new coronavirus. If camostat mesylate is combined with a CatB/L inhibitor called E-64d, the process of invading cells can be completely inhibited. Taken together with these results, the researchers concluded that the new coronavirus, like SARS virus, also needed CatB/L and TMPRSS2 proteases when invading cells.
Some protease inhibitors can inhibit new coronaviruses from entering the cell in cell experiments (Photo: Supplied)
The researchers point out in the paper that camostat mesylate, which inhibits the activity of TMPRSS2, has been approved for sale in Japan. Although it is used for completely unrelated indications, some of the findings in this study suggest that it may have antiviral potential and is a potential treatment idea. We look forward to scientists continuing to explore this direction and test this feasibility at an early date.