The Research of Coronavirus and Its Therapeutic Drugs (II)
3.1. The research of virus-based drug
3.1.1. Inhibitors of nucleic acid synthesis
(1) Ribavirin is a synthetic nucleoside antiviral agent discovered in 1972, which has a broad spectrum of antiviral activity and has inhibitory effects on DNA and RNA viruses. For the treatment of respiratory syncytial virus pneumonia in adults and children. Early in vitro studies have shown that the use of ribavirin can enhance the activity of interferon in vitro. Ribavirin, when used alone or in combination with interferon alpha, has anti-MERS-CoV activity in vitro. Clinical studies have shown that ribavirin and pegylated interferon α-2a treatment can significantly improve the 14-day survival rate of patients with MERS-CoV infection and slightly improve the 28-day survival rate. The timing of starting antiviral therapy is critical to the treatment of most virus-infected patients. Experimental data show that in the treatment of SARS-CoV, the treatment effect is better when ribavirin is used immediately after diagnosis, but no obvious effect can be observed when ribavirin is started 6 to 14 days after the onset of symptoms. The side effects of ribavirin limit its application to a certain extent. The use of high-dose ribavirin may be related to hemolytic anemia, neutropenia, teratogenicity and cardiopulmonary distress. In view of the efficacy of ribavirin in the treatment of diseases caused by SARS-CoV and MERS-CoV, it is expected to become one of the effective drugs for the treatment of coronavirus.
(2) Remidesivir (RDV, GS-5734) is a nucleoside analogue. As a drug under investigation, it has not been approved for marketing in any country. It can exert therapeutic effects by inhibiting the synthesis of viral nucleic acid and has antiviral activity. Antiviral nucleic acid analogs are treated by coronavirus exonuclease ExoN when they are integrated into viral RNA during the treatment of coronavirus infection, but RDV is resistant to ExoN, which is why RDV treatment on coronavirus is more effective than other nucleic acid drugs. Previously, RDV was mainly used as a test drug against Ebola virus for related research. It has a strong anti-filament virus effect in vitro, but the previous phase II/III clinical research results show that its effect may not be as good as the other two. Monoclonal antibody drugs (REGN-EB3 and MAb114). In vitro tests, RDV can effectively inhibit the activity of SARS-CoV and MERS-CoV, and RDV is the only therapeutic drug that can improve the pathological damage of lung tissue.
3.1.2. Protease inhibitors
(1) Lopinavir and ritonavir are the first-line drugs for clinical treatment of AIDS, mainly by combining with viral protease to inhibit protease function. Lopinavir-ritonavir is a compound tablet consisting of lopinavir and ritonavir. Lopinavir is a sensitive substrate for cytochrome CYP3A4 and P-glycoprotein, which can block the division of Gag-Pol polyprotein, and has a high protein binding rate in plasma. Ritonavir is a substrate of CYP3A4, P-glycoprotein and CYP2D6. By inhibiting HIV protease, the enzyme cannot break down the precursor of Gag-Pol polyprotein. Ritonavir can inhibit CYP3A-mediated lopinavir metabolism, resulting in a higher concentration of lopinavir. In vitro studies have shown that lopinavir and ribavirin can inhibit the replication of MERS-CoV and SARS-CoV.
(2) Darunavir (Prezista) is a second-generation HIV-1 protease inhibitor. The combination of darunavir with ritonavir and other retroviral drugs can be used to treat HIV infection. It can selectively inhibit the cleavage of HIV-encoded Gag-Pol polyprotein in virus-infected cells, thereby inhibiting virus replication. Darunavir is also safe and effective in special patient populations (including pregnant women, pediatrics, patients with HIV-2 infection and co-infected viral hepatitis). In vitro cell experiments showed that darunavir could significantly inhibit virus replication at a concentration of 300 μmol·L-1. Compared with the untreated group, the inhibition efficiency was 280 times.
(3) Type II transmembrane serine proteases (TMSPSS2) inhibitors may be used to block the infection of SARS-CoV-2 and then be used to treat COVID-19. ACE2 is a metallopeptidase, expressed on major viral target cells such as type II lung cells and intestinal epithelial cells, and its catalytic domain binds to the S protein of SARS-CoV with high affinity. For the infectivity of the virus, the cleavage of the S protein by the host cell protease is essential. TMSPSS2 can activate the spike protein of SARS by cleaving the spike protein on the cell surface, which in turn combines with ACE2 to enter the host cell. TMPRSS2 is expressed in ACE2-positive cells in human lungs. Cell experiments indicate that TMPRSS2 may play an important role in the transmission of SARS-CoV in the human respiratory tract.
Multiple studies have shown that 2019-nCoV is likely to bind to human ACE2 receptors and thus invade the human body. Many of the prevention and treatment drugs for 2019-nCoV are screened with the ACE2 receptor as a target. In view of the importance of TMPRSS2 in influenza virus and coronavirus infection, TMPRSS2 inhibitors may be used in clinical treatment.
3.1.3 RNA polymerase inhibitors
Favipiravir (Avignan) is a broad-spectrum antiviral drug that can selectively inhibit the RNA polymerase of influenza virus and is used for antiviral treatment of influenza A and B. It is converted into an active form of phosphoribosylation in the cell and is recognized as a substrate by viral RNA polymerase. Fapiravir is active against a variety of influenza viruses including A (H1N1) pdm09, A (H5N1) and A (H7N9) avian influenza viruses, and has a synergistic effect with oseltamivir. In addition to its anti-influenza virus activity, fapiravir also blocks the replication of many other RNA viruses, including alpha viruses, flaviviruses (yellow fever and West Nile virus), enteroviruses (poliovirus and rhinovirus), type A virus, respiratory syncytial virus and norovirus.
3.1.4 Membrane fusion inhibitor
Arbidol (Umifenovir) is a synthetic broad-spectrum antiviral compound used to prevent and treat human influenza A and B influenza infections and post-influenza complications. It has been used as an anti-influenza virus drug in many countries for decades. Abidor is active against many DNA/RNA and enveloped/non-enveloped viruses. By intercalating into membrane lipids, it inhibits membrane fusion between virus particles and plasma membrane and between virus particles and endosomal membrane. Compared with the untreated drug control group, Abidol can effectively inhibit coronavirus up to 60 times, and significantly inhibit the virus's pathological effect on cells.

To be continued in Part III…

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