Since the outbreak of the new pneumonia in mid-to-late December 2019, more than 200 countries in the worldhave been attacked by the virus. As of November 29, more than 61 million people worldwide have been infected with the virus, and the number is still increasing. Coronavirus is usually related to human acute respiratory infections. The SARS (Severe Acute Respiratory Syndrome) occurred in 2003 and the MERS (Middle East respiratory syndrome) occurred in 2012 are both caused by the coronavirus. The main transmission routes of the SARS-CoV-2 are respiratory droplet transmission and contact transmission.

SARS-CoV-2, SARS-CoV and MERS-CoV are all β-coronaviruses, so their genes are highly homologous.Two key antiviral drug targets, one antibody and vaccine target, and one detection reagent development key target were finally discovered by analyzing Nsp5 (3CL hydrolase), Nsp12 (RdRp), Nsp7, S protein, N Protein and other structures.

1 Targets of antiviral drugs

The targets of antiviral drugs discovered so far are Nsp5 (3CL hydrolase, also known as the main protease), and Nsp12 (RdRp, RNA-dependent RNA polymerase). Nsp5 is a key protease that prevents the production of viral proteins. The homology of Nsp5 gene of different coronaviruses reaches 96%, which makes Nsp5 the most attractive target for the development of antiviral drugs. RdRp is a key enzyme for viral RNA replication and the most conserved protein in viral evolution. After analysis and research, it is found that the sequence homology of the RdRp protein between SARS-CoV-2 and SARS is as high as 96%. The three-dimensional structure of the novel coronavirus RNA polymerase was obtained through homology modeling using the structure of SARS RNA polymerase, and some inhibitors were obtained by molecular screening with the enzyme as the target.

2 Targets of antibodies and vaccines

Because the binding of S protein (surface spike glycoprotein) to cell surface receptors is the beginning of coronavirus replication, S protein is one of the key targets for antibody and vaccine design. The SARS-CoV-2 S protein sequence was analyzed and studied, and it was found that it has high homology with the S protein of SARS, MERS and other coronaviruses. However, a special Furin-like cleavage site was found between the S protein S1 subunit and S2 subunit of SARS-CoV-2, which is not available in the S protein of SARS, MERS and other coronaviruses, so Furin protease can be used as a new target for anti-SARS-CoV-2 treatment. In addition, the S1 subunit of SARS-CoV-2 S protein has an upward spiraling receptor binding domain (RBD), which makes the binding force of S protein and the host’s key receptor angiotensin converting enzyme II (ACE2) stronger. Therefore, the RBD in the S1 subunit can be used as a key target for antibodies and vaccines.

3 Targets of detection reagents

N protein (nucleocapsid protein) is highly phosphorylated and highly hydrophilic, so it is relatively conservative in the passage process and can induce strong humoral and cellular immunity. It is the preferred target for detection. Most of the currently approved detection kits using nucleic acid detection methods use N protein as a target.

4. Research status of SARS-CoV-2 therapeutic drugs

Currently, there are no specific chemical drugs for preventing or treating SARS-CoV-2, and there is an urgent need to find potentially effective therapeutic drugs among existing drugs. There are two main strategies for the research and development of new coronary pneumonia chemical drugs: new use of old drugs-to verify whether the listed drugs can treat COVID-19; new use of "new" drugs-to verify whether unlisted drugs can treat COVID-19.

When looking for potential treatments for SARS-CoV-2 in old drugs, two strategies are generally adopted.One strategy is to directly fight viruses (such as arbidol),in vitro experiments have proven that arbidol has an inhibitory effect on SARS-CoV-2 . However, there is currently a certain controversy over the target of action and safety of Arbidol. Therefore, a number of clinical trials have been carried out for the drug to evaluate its effectiveness and safety in the treatment of new coronaviruses. The second strategy is to target host cells to enhance host immunity and block viruses from entering cells. For example, the "old" anti-malarial drug chloroquine phosphate (chloroquine) is recommended as a trial drug. In vitro experiments have shown that chloroquine phosphate can inhibit SARS-CoV-2, but may cause sudden death.

The representative of the new drug, Remdesivir, was originally an experimental drug developed by Gilead in the United States to combat Ebola virus. It is a ribonucleic acid-dependent ribonucleic acid polymerase inhibitor that inhibits RNA-dependent RNA polymerase (RdRp) thereby inhibits virus replication. However, in the Ebola virus treatment trial, Remdesivir was declared a clinical trial failure with a high mortality rate of 53% (93/175). However, several recent studies have found that Redecive can effectively inhibit SARS-CoV-2, and its EC50 for inhibiting SARS-CoV-2 reaches 0.77 μmol/L. The first confirmed case of new coronary pneumonia in the United States has significantly improved symptoms after using Radixivir. Subsequently, researchers at the University of California, Davis claimed that medical staff used Redecive again to cure a critically ill patient with new coronary pneumonia. So far, Remdesivir is considered to be the most promising drug to cure the new type of coronavirus pneumonia, and the WHO has listed it as the first of the four treatment options for the new type of coronavirus. However, on October 17, the WHO announced that the 2 phase 3 clinical trials of Redcivir showed little or no effect.

To be continued in Part II…