The COVID-19 virus is indeed new, but it is not new. The virus that is currently raging around the world is very similar to the virus that caused severe acute respiratory syndrome (SARS) from 2002 to 2003, so virologists have initially referred to it as SARS-CoV-2.
But 17 years apart, there are also a series of core differences between the two waves. The good news is that although the COVID-19 virus is more infectious, it seems less lethal than the early SARS virus. SARS-CoV-1 has infected about 8,000 people with a fatality rate of about one-seventh. The currently known SARS-CoV-2 virus (though still not finalized) is much lower and may be lower than one-seventh.
But the bad news is that SARS-CoV-2 spreads more widely than the original SARS-CoV-1, partly because many infected people have milder early symptoms and the COVID-19 virus has a longer incubation period. All in all, compared with SARS, people infected with COVID-19 virus are more likely to inadvertently transmit the virus to others.
To gain a deeper understanding of the reasons for this difference, researchers are in-depth analysis of the three-dimensional structure of the COVID-19 virus protein, especially the part responsible for infecting human cells and self-proliferating. The resulting insights are expected to provide important clues for the treatments and vaccine development being tested.
Striking spike structure
Today, awareness of the COVID-19 virus is rapidly increasing. As of now, the most interesting is the spike protein present in it: a protein that exhibits the shape of a spike under an electron microscope. Viruses carrying this type of protein will have a special corona structure, which is why the coronavirus name is derived.
So scientists are also focusing on these spikes because they realize that these structures play a vital role in infection. Spikes not only maintain the virus’s own traits, but also become a structural prerequisite for recognition, binding, and entry into host cells.
The virus’s first genetic sequence was officially announced to researchers worldwide on January 11. Less than six weeks later (February 19, this year), a laboratory research group led by structural biologist Jason McLellan of the University of Texas at Austin published a paper in the journal Science, prompting the SARS-CoV-2 virus The three-dimensional structure of tunin. A researcher at McLellan’s lab deduced the structure around the clock, saying that “the structure itself looks like a mushroom and has a clear head to stem distinction.”
The head of the spike (also known as S1) is the part that first attaches to the host cell. Specifically, it binds to the ACE2 receptor, which is located on the outer surface of certain tissue cells in the body, including all types of tissues inside the lungs. The normal function of ACE2 is, of course, not to help the virus complete penetration, but to achieve regulation of blood pressure in the organ. However, SARS-CoV-2 and its close relative, SARS-CoV-1, which broke out more than a decade ago, chose ACE2 as a breakthrough.
In both viruses, the S1 tip uses a series of amino acids called receptor structural motifs to recognize the ACE2 receptor and complete locking and penetration. Wang explained that it is interesting that the actual motif structure used by SARS-CoV-1 and SARS-CoV-2 is different. Overall, the amino acid sequences that make up these two viral spike proteins are about 80% identical, but the receptor-binding motif is only about 50% in common.
Because it plays a key role in recognizing the ACE2 receptor, the sequence and structure of this binding motif is likely to have a significant impact on the possibility of spike protein-receptor binding-researchers call this binding affinity. Another experiment reported in the same issue of Science showed that the binding affinity of SARS-CoV-2 spike protein to ACE2 is 10 to 20 times higher than that of SARS-CoV-1 spike protein. Wang said that this may explain why SARS-CoV-2 is far better than SARS-CoV-1 in terms of human-to-human infection ability. “But we need more strong evidence to confirm this.”
Ding Xiang Liu, a virologist at South China Agricultural University in Guangzhou, points out that because the specific structure of the ACE2 receptor depends on the specific species, the virus must undergo a large number of mutations to gain human infection. The virologist outlined the mechanism of interaction between human coronavirus and host in the Annual Microbiology Review.
Obviously, the existence of many different species of animal trading markets is the ideal environment for virus mutation testing. Liu pointed out, “So we should regulate this type of trading activity, especially the consumption of wild animals.”
Forced fusion
After spike proteins attach to the ACE2 receptor, scientists believe that the membranes around human cells may engulf the virus, introduce it into the interior, and transport it to the lysosome. The so-called lysosome is an enzyme-containing vesicle that cuts the protein of a potential intruder into safe and harmless fragments as part of an evolutionary defense mechanism.
However, the spike proteins of viruses such as SARS-CoV-1 and SARS-CoV-2 have begun to undergo targeted evolution, hoping to use this self-defense mechanism to invade cells. In fact, the two proteins can only perform the next step after they have been cleaved by one or more intracellular enzymes: the virus and the membrane surrounding the lysosome are brought closer together until they fuse. In this way, the genetic material in the virus can escape from the lysosome into the cell.
The genetic material of these viruses is RNA, not DNA. RNA is the same molecule in human cells that is used to pass genetic instructions from the nucleus to the site of protein building. Therefore, when the viral RNA is released from the lysosome, the cell will quickly function and build its designated protein structure, so that the virus can multiply and expand.
Liu explains that the danger is also here. Although we usually regard the immune system as an important carrier to protect the human body, in some patients, a large amount of viral RNA and proteins produced will cause the immune system to start interesting operations, eventually leading to serious diseases and even death. Liu pointed out that this “excessive” immune response is “the main cause of tissue damage and organ failure,” and many COVID-19 patients have lost their lives because of this.
Vaccine virus development
Currently, several trials are testing existing drugs for the treatment of other diseases, including certain viral infections, and hope to find options that can inhibit the SARS-CoV-2 virus (such as interfering with the self-replication process of the COVID-19 virus). ). However, many scientists believe that the most reliable method is to develop a new vaccine to help our immune system better resist the initial infection caused by SARS-CoV-2.
Teams are working to develop this vaccine, which may contain dead or attenuated viruses, or specific fragments of viral proteins, plus several other substances that stimulate the immune system to respond normally. The human body will generate antibodies against the contents of the vaccine that block molecular binding, marking similar substances as viruses and assigning white blood cells to destroy them.
But in addition to the traditional ideas above, vaccines also have other ways to destroy the structure of SARS-CoV-2 protein. For example, antibodies attached to the spike protein receptor binding motif may prevent the protein from binding to the ACE2 receptor, thus preventing the virus from infecting human cells. Antibodies that bind to other parts of the spike protein can prevent the virus from fusing with the cell membrane, thereby preventing the genetic material of the virus from being incorporated into the cell’s protein composition process. Of course, it is not enough to just obtain spiked protein-binding antibodies; some antibodies will not affect the actual function of the protein, while others will even enhance the function of the target protein.
Wang explained that mass production of such vaccines containing sufficient quantities of proteins, such as SARS-CoV-2 spike protein, is often difficult and costly. “Proteins are difficult to make and it is not easy to maintain their quality for a long time.” To this end, some companies may be inspired by the virus itself and adopt another solution. Instead of using proteins directly, they chose RNA that contains instructions for protein construction. Once human cells build this protein, the immune system is able to produce the corresponding antibodies. Scientists are currently testing this RNA-containing vaccine, where the role of RNA is to provide the genetic code for the SARS-CoV-2 spike protein.
Wang hopes that knowledge of the structure of spike proteins will lead to more targeted treatments. By creating a new vaccine, researchers hope to be able to introduce a portion of spike proteins that have been bound to antibodies, or allow human cells to construct this part of the RNA instructions themselves, thereby completing the blocking of the virus.
Antibody source
Currently, about 35 companies and academic institutions around the world are working on vaccines. But it still takes time, and the vaccine will have no effect on already infected populations.
Therefore, in addition to trying existing therapies, some researchers are also trying to prepare antibodies against spike proteins in the laboratory and inject them into the body as drugs. The entire research process can be accomplished in a variety of ways, such as injecting viral spike proteins into mice that have been genetically modified to produce human-like antibodies, and then testing to see if the antibodies they produce can effectively block virus transmission.
In a non-peer-reviewed paper published on March 12, a Dutch research team led by molecular biologist Frank Grosveld and virologist Berend-Jan Bosch announced that this method creates an antibody (their total 51 antibodies were created) seems to be very effective. The experimental results of the research team show that this antibody named 47D11 can bind to SARS-CoV-1 and SARS-CoV-2 spike proteins, thereby blocking existing and other SARS-CoV-based spike proteins. The virus infects normal cells. (The exact mode of action of this antibody is not yet known. From observation alone, although it can be linked to the receptor-binding portion of spike protein, it does not seem to actually prevent the spike protein from binding to the ACE2 receptor.)
The team is currently testing the antibody to see if it can protect mice and other animals from infection. If the experiment is successful, the next step is to prove its safety and effectiveness in clinical trials. More importantly, this research is also expected to lead to other more efficient virus testing methods.
Wang said, “At present, we cannot say whether antibodies can be used as effective treatments. But it is clear that this is a promising direction.”
Ultimately, these inventions are expected to lead to a new vaccine that may contain a portion of the protein already bound to the 47D11 antibody, or a corresponding protein synthesis instruction. Wang pointed out that the method of injecting therapeutic antibodies directly into the human body often has cyclical limitations, which means that we need regular supplements to maintain the therapeutic effect. Correspondingly, a good vaccine can guide the human body to make antibodies when needed, so as to achieve the best prevention and treatment goal of one injection and lifelong immunity.

Leave a Reply

Your email address will not be published. Required fields are marked *