The Drug Targets of Anti-New Coronavirus Pneumonia and

The Mechanism of Existing Drugs (III)

Known antiviral mechanism of Arbidol: ① Prevent virus from entering cells: Arbidol inhibits virus entry by interfering with clathrin-dependent endocytosis; Arbidol inhibits viral lipid membrane-endosomal vesicle membrane The fusion of fusion, play a role of membrane fusion inhibition. . ②Induces interferon: Arbidol induces the production of interferon by activating 2,5-oligoadenylate synthase (OAS), degrades viral mRNA, and prevents viral replication. It has a strong effect of inducing interferon, which can induce sufficient interferon production in the local mucosa of the respiratory tract in a short time (24h), and form a broad-spectrum antiviral state in the local respiratory tract on the fourth day. Improve the body’s immune function and the ability to swallow viruses, faster than the injection of the vaccine (usually 14 days). ③Improve immunity: Arbidol can activate phagocytes and enhance non-specific immune disease. Arbidol can significantly improve multiple immunological parameters (CD4+, CD8+, B cells and serum immunoglobulin) in immunocompromised patients.

Arbidol has been used to treat influenza for more than 10 years. There are no reports of drug resistance and no drug-resistant strains have been found in the population. It can be seen that Arbidol has multiple antiviral mechanisms, unlike single-target antiviral drugs. But these are still to be studied.

2.3. Ribavirin

Ribavirin is a purine nucleoside analog with a broad-spectrum antiviral effect. It may have multiple mechanisms of action, including lethal mutagenesis, obligate or non-obligate chain termination, and by inhibiting inosinic acid- The synthesis of 5-phosphate dehydrogenase (its target is RdRP), which blocks the conversion of inosinic acid to guanylic acid, thereby preventing the replication of RNA and DNA viruses. The last step in this reaction chain is that the mutation of the RNA gene is the deadliest and most deadly A critical step. . Therefore, ribavirin has a good antiviral effect clinically, and it has an inhibitory effect on DNA virus and RNA virus.

2.4. Lopinavir/ritonavir

Lopinavir is a human immunodeficiency virus 1 (HIV-1) protease inhibitor, often used in combination with ritonavir to increase the half-life of lopinavir by inhibiting the metabolism of cytochrome P450 enzymes. Cytochrome P450 is metabolized by the enzyme to increase the half-life of lopinavir. The results of in vitro experiments show that lopinavir/ritonavir can inhibit the replication of coronavirus to a certain extent. Chinese scholars have used marmoset animal models to find that the combination of lopinavir/ritonavir and interferon-β in the treatment of MERS-CoV infection has a better effect than the control group.

2.5. Ambroxol

Ambroxol is a mucolytic agent. As a drug that has been used in clinical practice for a long time, it has high safety. It not only has phlegm and expectoration effects, but also can stimulate the respiratory tract type II alveoli when used in large doses. Cells synthesize and secrete alveolar surface-active substances, and also have antioxidant and anti-inflammatory effects, and they can prevent and treat pulmonary fibrosis. In particular, ambroxol, as one of the potential ACE2 receptor binding agents, can prevent or alleviate the acute lung injury and even acute respiratory distress syndrome caused by 2019-nCoV. It slows down kidney and heart damage and provides useful treatment ideas. Therefore, ambroxol is also recommended as one of the drugs for the treatment of COVID-19.

Three possible mechanisms of ambroxol in preventing and treating COVID-19: ① Ambroxol can promote the synthesis and secretion of alveolar surfactants in type II alveolar cells. Type II alveoli expressing ACE2 are likely to be the target cells of 2019-nCoV infection. Ambroxine stimulates the synthesis and secretion of alveolar surfactant by type II alveolar cells of the respiratory tract, which can prevent lung inflammation and maintain alveolar structure. -ARDS caused by nCoV plays an important role in prevention and treatment. And studies have shown that when ARDS appears in the body, alveolar macrophages, granulocytes, and monocytes are activated, and the production of endogenous oxidants in the lungs increases, so a large amount of oxygen free radicals are produced, and ambroxol can inhibit the ultra-oxide anions and hydrogen peroxide are generated to reduce oxidative stress damage. ②Ambroxol has anti-pulmonary fibrosis effect. Ambroxol can inhibit the production of cytokines and arachidonic acid products, reduce the release and aggregation of neutrophils and macrophages, play an anti-inflammatory effect, and thus slow down the process of pulmonary fibrosis. ③ As a possible ACE2 combination Ambroxol can inhibit the binding of the viral spike S protein to the cellular ACE2 receptor, thereby inhibiting the cell invasion of 2019-nCoV.

2.6. Redcivir

The symptoms have improved significantly. Remdesivir is a nucleoside analog developed by Gilead. It is mainly used as a test drug against Ebola virus (Ebolavirus, EBOV) and Marburg virus (Marburg virus). It is currently in vitro and In the in vivo animal model test, it has antiviral activity against both MERS-CoV and SARS-CoV. For the same coronavirus, 19-nCoV, recent studies have also shown that Remdesivir exhibits inhibitory activity in in vitro experiments. Desivir exhibited inhibitory activity in in vitro experiments, with an IC50 value of 50 and a value of 0.77 μmol/L. At present, Remdesivir has not passed a complete clinical trial and has not been approved for marketing in any country. Its actual effect and safety in humans still need to be evaluated.

Coronavirus has no effective antiviral activity due to the 3'-5' exonuclease properties, and remdesivir can effectively inhibit the coronavirus through the complete exonuclease proofreading. Its triphosphate resultant product competes with adenosine triphosphate (ATP) to inhibit the activity of RNA-derived RNAPolymerase (RdRP), especially the activity of the respiratory syncytial virus (RSV) polymerase, and metabolizes and synthesizes active nucleoside three in a variety of human cells. Phosphoric acid (NTP), NTP as an alternative substrate, binds to the RNA chain of the new virus, causing the virus to mature and terminate prematurely.

In summary, the current research on the 2019-nCoV virus is not very clear, and the mechanism of action and therapeutic effects of related drugs need to be further studied and verified. To be further studied and verified. However, by using computer simulation techniques such as molecular docking and binding free energy calculations and deep learning models, some potential inhibitors against 2019-nCoV have been found. It can be seen from the analysis of the literature that, based on the highly conserved and replicated gene sequence on 20119-nCoV, it targets S protein and ACE2 receptor, or the main protease (Mpro) for cleavage and replication of RNA, TMPRSS2, cathepsin L, chymotrypsin-like protease (3CLpro), papain-like protease (PLpro) and RdRP, etc. as targets to develop antiviral drugs may be the direction of future research.

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