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How far is the new crown cure from us?

   The new crown epidemic broke out for more than two years and affected billions of people around the world. The vaccine that people had high hopes for failed to completely control the epidemic. Therefore, people shifted their expectations to specific drugs. If specific drugs are available, even if they are sick, He will recover soon, and we won't have to talk about the disease's discoloration. So, how long will it take for the cure to come?

How to do antiviral drugs


  We already know that virus invasion of cells is roughly divided into three stages: entering cells, dividing and replicating, and finding a home. If we can interfere with any of these steps, we will achieve the purpose of anti-virus. Pharmaceutical experts are in the same vein.

  HIV has the "key" to open the door of human immune T cells. When it encounters T cells, it will quickly open a small opening in its cell membrane that only genetic material RNA can enter. Then HIV will abandon its own protein coat, leaving only RNA "alone", and start to divide and replicate arbitrarily in T cells. The anti-HIV drug enfuvirtide prevents this outrageous act of "staying empty-handed," which binds to the virus's protein coat and tightly wraps the viral RNA when it wants to break free. That way, viral RNA can't get inside the cell.

  We say that the virus comes empty-handed when it invades human cells, which means that it can only use substances provided by the human body when it wants to divide and replicate, including the raw material nucleosides for synthesizing DNA or RNA. Therefore, we can provide some pseudonucleosides to the virus. When the virus uses these pseudonucleosides to synthesize genetic material, its subsequent physiological processes, such as replication, translation and assembly, cannot proceed normally, and the virus will gradually disappear. These "pseudonucleosides" are called nucleoside analogs, including remdesivir, lamivudine, etc., and they all have a certain effect on viruses that use similar nucleoside raw materials.

  Because the virus camps for parasitic life (camps for parasitic life: living in or on the body of other living organisms, relying on the host to provide them with nutrients), once there is no host, it will die soon, so preventing the virus from finding a home is also an issue. Very common strategy. When the flu virus has drained the cell's nutrients and needs to leave the cell, it uses a "key" called neuraminidase to open the cell's door so that the offspring virus can escape from the cell and continue looking for the next victim. The antiviral drug oseltamivir works against neuraminidase, which cuts it off and traps the virus in a cell.

How to do the new crown special medicine


  Maybe you want to say, since there are so many methods and so many antiviral drugs, why can't one be used to fight the new crown virus?

  This is because viruses are different from other pathogens - bacteria or fungi. Their genetic material is variable, they do not have a common structure or protein, and they are constantly changing even during transmission. One drug cannot fight multiple viruses. There is no way to scale up efficacy by modifying the drug, only one-to-one studies can be done.

  The cell door lock that matches the "key" of the new coronavirus is called ACE2. The virus enters the cell by unlocking it. Existing antiviral drugs cannot stop this process. Therefore, if we want to start pharmaceuticals from the direction of blocking the virus from entering the cell, we need to re-engineer it. Find available compounds. Unexpectedly, this potential specific drug falls on the blood pressure drug angiotensin I. As a receptor for ACE2, it can replace the new coronavirus and bind to cells, so that the virus cannot open the door and enter the cell. May reduce cell casualties. However, it is still unclear whether this drug can really treat new coronary pneumonia, and what side effects will it produce. It can be said that there is still a long way to go to make drugs that can prevent the new coronavirus from entering cells.

  In contrast, the effect of nucleoside analogs on the new coronavirus is more obvious. In early 2020, in a large-scale three-month trial, clinicians demonstrated that remdesivir could speed up the recovery of new crown patients. However, the effect of remdesivir is also very limited, and in other clinical trials, the use of remdesivir did not work. The National Institutes of Health's antiviral drug research and development team is developing another antiviral drug that uses the same strategy. This is an easy-to-synthesize oral drug that has been shown to speed up the clearance of the new coronavirus and has a certain degree of safety. Sex, has now entered clinical trials.

  In addition to nucleoside analogs, drug companies are trying another way to inhibit viral replication and division. US pharmaceutical company Pfizer is testing a drug called PF-07304814, a molecule that inhibits a protein critical for coronavirus replication, the major protease (Mpro), whose inactivation prevents the virus from assembling into its entirety body. Pfizer started the research and development of related drugs when the SARS virus appeared in 2003, so drug trials have progressed rapidly and have entered the clinical trial stage. Swiss drug company Novartis is also working on a pan-coronavirus inhibitor for Mpro, but it is just getting started.

  A multinational cooperative team in Singapore and South Korea has proposed a new broad-spectrum antiviral strategy: enveloped viruses not only have a protein coat, but also a lipid membrane wrapped around the capsid, which can be killed by disrupting the lipid membrane. Virus. There are many types of enveloped viruses, including coronaviruses, filoviruses, retroviruses, etc. Therefore, the development of such drugs can be effective against many viruses at the same time. They have developed a small peptide drug that punches holes in the lipid inclusions surrounding enveloped viruses, and may be the dark horse of antiviral drugs.

What are the difficulties in the development process


  It seems that the research and development of the new crown special medicine is progressing smoothly, and it seems that we will soon be able to use the special medicine, but this is not the case.

  Antiviral drugs are different from vaccines, which are essentially non-pathogenic viruses that we already know a little about in the body, and antiviral drugs, which are newly discovered or synthetic substances , it interacts with the many molecules in the human body, we do not fully understand. Therefore, we need to conduct multiple rounds of drug experiments, including both in vitro cell experiments and animal experiments, as well as in vivo clinical experiments.

  The effects of drugs in vitro and in vivo are not exactly the same. It is possible that drugs that are harmless in vitro may have toxic and side effects when they enter the human body; it is also possible that drugs that are effective in vitro may not achieve the desired therapeutic effect after entering the human body. This is because there are fewer drug target molecules involved in in vitro experiments, which makes it easier to evaluate drug efficacy. However, there are thousands of molecules in the human body, and many molecules have similar structures. After the drug enters the human body, in addition to binding to the target molecule In addition to producing medicinal effects, it may also interact with other molecules with similar structures.

  In the human body, changes in the structure and function of drug molecules may occur, which may lead to drug failure, excessive efficacy, and unexpected side effects. For example, angiotensin I, which is used to lower blood pressure, will be rapidly converted into angiotensin II in the body, which will cause vasoconstriction and increase blood pressure. Moxifloxacin, which is used to treat infection, will also act on potassium ion channels. Cause arrhythmia, etc. These consequences are not known by in vitro experiments.

  In order to ensure drug safety, new drugs need to go through 4 phases of clinical trials, gradually increase the number of patients participating in the trials, further determine the safety of the drug, and evaluate the effectiveness of the drug at the same time. Recruiting a large number of patients is itself a very time-consuming task, and the ethical difficulties of human clinical trials further increase the difficulty and length of the experiment. This set of experimental procedures usually takes 5 to 10 years.

  When all these tests are passed and the special drug is finally on the market, there may be bad news: the virus has mutated. Viruses are known to be very good at mutating, and drugs that mutate are likely to fail. Influenza viruses, for example, can spread among many animals, increasing the speed and extent of virus mutation. Before the mutation, oseltamivir had a good effect on influenza virus, but in recent years, the neuraminidase of influenza virus that caused epidemics such as bird flu and swine flu has undergone huge changes, and the effect of oseltamivir is not as good as before. .

  If the new coronavirus mutates fundamentally like the flu virus, the above process will be repeated, and the anti-new coronavirus drugs will be farther away from us. Therefore, no one can say now when the new crown special medicine will be available, and scientists can only do their best.

Multiple Ways to Eliminate Viruses


  To fight a wide variety of viruses, antiviral drugs can target highly conserved features of the virus itself, or they can interfere with the biological processes in the host that the virus uses to infect cells and spread. Here are some strategies that researchers are working on.


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