Since the outbreak of the novel coronavirus (2019-nCoV) epidemic, how to rapidly develop and prevent the virus has been a hot issue of concern to the industry and the public. A review was published in Nature Reviews Drug Discovery magazine, which explores treatment options for 2019-nCoV. The authors said that, given the urgency of the need for 2019-nCoV therapy, this article mainly focused on repurposing existing antiviral therapies for 2019-nCoV. Let's take a look at the exciting content of this article.
Features of Novel Coronavirus (2019-nCoV)
2019-nCoV is a single-stranded RNA, positive-stranded, enveloped beta coronavirus. Similar to SARS and MERS, its genome encodes non-structural, structural, and accessory proteins. Non-structural proteins include 3-chymotrypsin-like protease, papain-like protease, helicase, and RNA-dependent RNA polymerase (RdRp). Structural proteins include spike glycoproteins.
Spike glycoprotein is an indispensable part that mediates virus invasion into cells, while the other four non-structural proteins play a key role in virus proliferation. Therefore, these five proteins are considered as important targets for the development of antiviral drugs.
The initial analysis of the genomic sequences of the 2019-nCoV showed that the catalytic sites of the four 2019-nCoV enzymes are highly conserved and have high levels of sequence similarity to the enzymes in SARS and MERS. Furthermore, analysis of the protein structure suggests that the drug-binding "pockets" of neocrown virus, SARS, and MERS virus enzymes may be conservative. Therefore, there are reasons to consider reusing existing MERS and SARS inhibitors for 2019-nCoV.
Potential repurposing candidates for 2019-nCoV
Virally targeted agents
Nucleoside analogues that have been approved and are under investigation may have the potential to treat 2019-nCoV. They include favipiravir, ribavirin, remdesivir, and galidesivir. Nucleoside analogues are usually derivatives of adenine or guanine. They can be used by RdRP to synthesize RNA strands, but after integration into the RNA strand, it will block the continued synthesis of the RNA strand and allow the RNA strand synthesis to terminate prematurely. They can be used to treat a broad spectrum of RNA viruses, including coronaviruses.
Fapilavir is a guanine analogue that has been approved for the treatment of influenza virus infection. It can also effectively inhibit Ebola, yellow fever, chikungunya, norovirus, and enterovirus. A recent study showed that in vitro cell line experiments, it achieved an EC50 of 61.88 µM for 2019-nCoV. Currently, this antiviral therapy has entered clinical trials in combination with interferon alpha or baloxavir marboxil (an approved anti-flu drug) to treat patients with 2019-nCoV.
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Ribavirin is a guanine analogue approved for the treatment of hepatitis C virus (HCV) and respiratory syncytial virus (RSV). It has been evaluated in patients with SARS and MERS, however it can cause severe anemia at high doses. Whether this drug has sufficient activity for 2019-nCoV has not been determined.
Remdesivir is a prodrug of adenine analogs. The structure of the drug under investigation is similar to that of the approved HIV reverse transcriptase inhibitor tenofovir alafenamide. Remdesivir has shown good activity against MERS and SARS in cell culture and animal models and has been used in clinical trials to treat Ebola virus. A recent cell culture study showed that this candidate drug inhibited neocoronavirus in the cell line with an EC50 of 0.77 µM. At present, two phase 3 clinical trials have been initiated to test the efficacy of Remdesivir in the treatment of patients with 2019-nCoV, which is expected to be completed in April this year.
Galidesivir (BCX4430) is an adenine analogue originally developed to treat hepatitis C virus. It is currently undergoing safety testing in early clinical studies and evaluating its effectiveness in treating yellow fever. It has shown activity against a variety of RNA viruses in preclinical studies, including SARS and MERS.
It has been reported that the protease inhibitors (disulfiram, lopinavir and ritonavir) that have been approved show activity against SARS and MERS. Disulfiram can inhibit papain-like proteases of MERS and SARS in cell culture assays, but clinical evidence is currently lacking.
Clinical trials testing HIV protease inhibitors (such as lopinavir and ritonavir) in 2019-nCoV infected patients have been initiated. Lopinavir and ritonavir were originally thought to inhibit the 3-chymotrypsin-like protease of SARS and MERS, and have been associated with improved clinical outcomes in patients with SARS in non-random open-label clinical trials. However, whether HIV protease inhibitors can effectively inhibit 2019-nCoV's 3-chymotrypsin-like protease remains inconclusive. Because HIV protease belongs to the family of aspartic proteases, and 2019-nCoV protease belongs to the cysteine protease family. Furthermore, HIV protease inhibitors are optimized for the specific structure of the catalytic site of HIV protease 2-mer, which is not available in 2019-nCoV.
Spike glycoprotein is also an attractive target. Griffithsin is a lectin extracted from red algae that binds to oligosaccharides on the surface of different viral glycoproteins, including HIV glycoprotein 120 and the spike glycoprotein of SARS virus. Griffthsin's colloidal and enema dosage forms have been used in phase 1 clinical trials to prevent HIV infection, but as a means of treating or preventing 2019-nCoV, its efficacy and delivery system still need to be re-evaluated.
PEGylated interferon alpha-2a and -2b have been approved for the treatment of hepatitis B virus and hepatitis C virus infections. They may be used to stimulate the innate antiviral response in 2019-nCoV infected patients. Clinical trials have been initiated to test the efficacy and safety of PEGylated interferon and ribavirin combination therapy approved for the treatment of hepatitis C virus in patients with 2019-nCoV infection. However, it is unclear whether pegylated interferon and nucleoside analogs will produce a synergistic effect in the treatment of 2019-nCoV. Because subcutaneous injections of interferon are associated with multiple side effects, this combination therapy requires close monitoring of patients. And depending on the patient's response, it may be necessary to reduce the dose or discontinue treatment.
Small molecule drugs that have been approved to treat other human diseases also have the potential to modulate the interaction between 2019-nCoV and the host. For example, chloroquine, an immunomodulator that has been approved, has shown 2019-nCoV inhibition in cell lines (EC50 of 1.13 µM). It is currently being tested in an open-label clinical trial. Nitrozoxanide, which is approved for diarrhea, also shows 2019-nCoV inhibitory activity in cell lines (EC50 of 2.12 µM). However, it is worth mentioning that, although researchers have made many attempts in the development of small-molecule drugs targeted at the host in the past 50 years, only one drug has been approved by the FDA, which is maraviroc for treating HIV.
Conclusion How to quickly find effective ways to treat 2019-nCoV is a major challenge that researchers need to face. Because of the known safety characteristics of existing antiviral drugs and their activity against related coronaviruses, the reuse of these drugs may be an important near-term strategy for 2019-nCoV.
In addition to the drug candidates mentioned above, a number of clinical trials have been conducted in China to evaluate the effects of other treatment options, including umifenovir, oseltamivir, and ASC09F. In addition, more than 50 existing MERS and / or SARS inhibitors can be used by virus-resistant research institutions to screen potential therapies for 2019-nCoV.
In this article, the authors also collected information on more than 60 potential 2019-nCoV treatment options. You can visit the Nature Reviews Drug Discovery website to download a list of information about potential treatment options.
Huateng Pharmaceutical has completed the kilogram-level synthesis of multiple anti-2019-nCoV infection candidate drugs, and preparation work is ongoing.
The 2019-nCoV outbreak once again underscores the importance of developing broad-spectrum antiviral therapies against coronavirus. We look forward to the prevention and control of viral transmission by people around the world to control the further spread of the epidemic, and we also hope that clinical studies will soon find effective treatments for 2019-nCoV.