In a prompt response to Coronavirus Disease 2019 (COVID-19), researchers and scientists now spares no effort in attempting to find any effective therapies or vaccines. It is no easy task, indeed. However, after conducting a lot of research and exploration, scientists finally find there are a few potentially effective drugs that can be used to fight the new coronavirus in addition to Kelizhi, which was proved effective in preliminary tests.

1. Remdesivir

Remdesivir (RDV, GS-5734) is a new nucleoside analog antiviral drug developed by Gilead. Nucleoside analogs can exert antiviral therapeutic effects by inhibiting viral nucleic acid synthesis. RDV is currently being mainly used as a test drug for Ebola virus, and it has strong anti-filovirus effects in vitro. Phase III clinical trials have been completed. A case of Ebola patient was reported in the Lancet magazine in 2016 [2]. The 39-year-old nurse from Scotland was unfortunately infected during humanitarian work and was hospitalized for meningitis. In 14 days after receiving the experimental treatment for RDV, the virus level in the cerebrospinal fluid slowly decreased to undetectable and eventually recovered.

Subsequent research found that RDV is not only effective against filamentous viruses such as Ebola virus, but also inhibits respiratory syncytial virus, coronavirus, Nipah virus, and Hendra virus. By coronavirus culture of human lung epithelial cells, RDV was found to have a strong antiviral effect. For both MERS-CoV and SARS-CoV, their half effective concentrations (EC50) were 0.07 μM. The EC50 values for MERS-CoV and SARS-CoV are 8 μM and 17 μM, respectively [3]. Animal experiments show that preventive and early use of RDV can significantly reduce the viral load of lung tissue in SARS-CoV and MERS-CoV infected mice, while improving lung function and relieving symptoms. Further research has found that RDV performs better in in vitro cell culture and animal experiments compared with Kelizhi combined with IFN-β, and is the only therapeutic drug that can improve the pathological damage of lung tissue [4]. From the current research data, Remdesivir may be the most promising anti-coronavirus drug. However, there are no related studies on the safety and effectiveness of RDV in humans.

2. Kelizhi (Lopinavir / Ritonavir)

In clinical practice, we prescribe Kelizhi to HIV-infected people and combine it with other anti-HIV drugs to form a so-called "cocktail therapy" to treat HIV. The main ingredient of Kelizhi is lopinavir, which is a protease inhibitor. It mainly inhibits the function of protease by combining with viral protease. In this way, the Gag-Pol polyprotein produced by the virus replication process cannot be successfully lysed and the virus produced pellets are immature and non-infectious. Lopinavir alone has poor bioavailability. If combined with another protease inhibitor - ritonavir, ritonavir can inhibit the liver's catabolism of lopinavir, which can increase the concentration of lopinavir in the blood, thus improving the effect of antiviral therapy. The combination of lopinavir and ritonavir is Kelizhi, which was approved by the US FDA for antiviral treatment of AIDS in 2000. Although taking drugs will cause side effects such as diarrhea, vomiting and high blood lipids, the antivial effect is good and the resistance barrier is high. Therefore, it is still currently used as a main anti-HIV treatment drug in clinics.

As coronavirus replication also requires the action of viral proteases, so if lopinavir, ritonavir and other protease inhibitors against HIV can also bind to the coronavirus protease to inhibit its normal function, they can exert an anti-coronavirus effect. Previous in vitro studies have shown that lopinavir / ritonavir can inhibit MERS-CoV and SARS-CoV replication. When the SARS epidemic broke out, scholars from Hong Kong, China, used Kelizhi combined with ribavirin to treat 41 SARS patients, and found that compared with 111 patients treated with ribavirin, the combined treatment lowered the risk of adverse events such as acute respiratory distress syndrome (ARDS) or death (2.4% vs 28.8%) occurred 21 days after the onset of symptoms [1]. A clinical study called MIRACLE is ongoing to assess whether Kelizhi combined with IFN-β is indeed effective and can improve the clinical outcomes of patients with MERS-CoV.

3. Interferon

Japanese scientists discovered the "viral interference phenomenon" in 1954. It means that after a virus infects a cell, the cell can synthesize and secrete a protein called interferon to interfere with virus replication and enhance the antiviral ability of nearby cells. Human interferons include type I and type II. Type I interferons include IFN-α, β, κ, λ, etc., which are synthesized and secreted by infected virus cells. Type II interferons include IFN-γ, which are mainly synthesized by T lymphocytes. At present, IFN-α is mainly used in clinical antiviral therapy, which can bind to specific receptors of virus-infected cells, thereby activating antiviral protein genes, and then synthesizing various antiviral proteins. These antiviral proteins can cut viral nucleic acids, inhibit viral protein synthesis, and inhibit viral assembly, thereby inhibiting viral replication. IFN-α interferon also has a powerful immune regulatory function, can activate natural killer cells, macrophages and other immune cells, and enhance the host's immune defense function.

Clinically, IFN-α has been widely used in chronic hepatitis B, chronic hepatitis C and other diseases. It can also be used topically to improve the treatment effect of herpes simplex virus infection and human papilloma virus infection. The “Pneumonitis Diagnosis and Treatment Scheme for New Coronavirus Infection (Trial Version 3)” states that IFN-α aerosolized inhalation can be used as an anti-new coronavirus treatment to improve the virus clearance effect of respiratory mucosa in patients. In vitro studies on the Middle East Respiratory Syndrome Coronavirus (MERS-CoV) and Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) have found that IFN-α and IFN-β have inhibitory effects on the coronavirus. Among each of their subtype, IFN-β1b type has the best antiviral effect on MERS-CoV.

4. Cyclophilin inhibitor

Studies have shown that the nucleocapsid protein of SARS-CoV binds tightly to Cyclophilin A in human cells, thereby helping its infection and replication. In 2011, Swiss and American scientists reported that cyclosporine (CsA) can inhibit coronavirus. In the same year, German and British scientists proved that the host Cyclophilins are possible drug targets of coronavirus [5]. The research drug STG-175 is a novel cyclosporine derivative, which has no immunosuppressive effect. It is a highly active Cyclophilin inhibitor in the same class of known compounds, and may be developed into a broad spectrum of anti-coronary viral drugs [6].

5. Other potentially effective drugs

Other nucleoside analogs, such as ribavirin and fapilavir, have broad-spectrum antiviral effects in vitro and theoretically have some anti-coronal virus activity. However, because the coronavirus's exonuclease has the function of proofreading RNA, the effect of drugs such as ribavirin to prevent viral nucleic acid replication will be greatly weakened. Nucleoside retroviral inhibitors used in the treatment of AIDS, such as tenofovir and lamivudine, have the effect of inhibiting RNA synthesis, and it is worth observing whether it can exert anti-coronal virus treatment effect. Related studies can be conducted to further verify their effectiveness in combating Coronavirus Disease 2019 (COVID-19).

Reference:
1. Jacobs M, Rodger A, Bell D J, et al. Late Ebola virus relapse causing meningoencephalitis: a case report[J]. The Lancet, 2016, 388(10043): 498-503.
2. de Wilde A H, Jochmans D, Posthuma C C, et al. Screening of an FDA-approved compound library identifies four small-molecule inhibitors of Middle East respiratory syndrome coronavirus replication in cell culture[J]. Antimicrobial agents and chemotherapy, 2014, 58(8): 4875-4884.
3. Sheahan T P, Sims A C, Leist S R, et al. Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV[J]. Nature Communications, 2020, 11(1): 1-14.
4. Chu C M, Cheng V C, Hung I F, et al. Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings[J]. Thorax, 2004, 59(3): 252-256.
5. Pfefferle S, Schöpf J, Kögl M, et al. The SARS-coronavirus-host interactome: identification of cyclophilins as target for pan-coronavirus inhibitors[J]. PLoS pathogens, 2011, 7(10).
6. Gallay P A, Chatterji U, Bobardt M D, et al. Characterization of the Anti-HCV Activities of the New Cyclophilin Inhibitor STG-175[J]. PloS one, 2016, 11(4).

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