Full text compilation! A novel coronavirus 2019-nCoV selection is introduced in the Nature journal review.

Novel coronavirus (BIOON/---) was released rapidly in February 11, 2020, and since February 11, 2020, the new coronavirus (2019-nCoV) was identified in severe pneumonia patients in China's Wuhan As of February 10, 2020, 2019 ncov cases have been reported in 25 countries on four continents, with more than 40000 confirmed cases and an estimated risk of death of about 2% Unfortunately, there are no drugs or vaccines approved for the treatment of human coronavirus Several methods can be envisaged to control or prevent the emergence of 2019-ncov infection, including vaccines, monoclonal antibodies, oligonucleotide based therapies, peptides, interferon therapy and small molecule drugs However, new interventions may take months to years to develop In view of the urgency of the 2019-ncov epidemic, Dr Guangdi li of Xiangya School of public health, Central South University of China and Erik de of the leiga Institute of medicine, Catholic University of Leuven, Belgium Based on his experience in the treatment of two other human coronavirus infections, severe acute respiratory syndrome (SARS CoV) and Middle East respiratory syndrome (mers COV), Dr clercq focused on the reuse of approved or under development therapies for HIV, hepatitis B virus (HBV), hepatitis C virus (HCV) and influenza The potential of antiviral agents for viral infections The results were published in the Nature Reviews Drug Discovery on February 10, 2020 in the form of a review article titled "theoretical options for the 2019 Novell corona (2019 ncov)" Characteristics of 2019 ncov 2019 ncov is a kind of enveloped justice single stranded RNA type B coronavirus Similar to SARS CoV and mers CoV, the 2019-ncov genome encodes non structural proteins (such as 3-chymotrypsin like protease, papain like protease, helicase, RNA dependent RNA polymerase), structural proteins (such as spike glycoprotein), and helper proteins (Figure 1) Figure 1 Potential drug targets of b-coronavirus, picture from nature reviews drug discovery, 2020, DOI: 10.1038/d41573-020-00016-0 The four non structural proteins mentioned above are key enzymes in the virus life cycle, and the spike glycoprotein (s) is essential for the virus cell receptor interaction in the process of virus entry into cells Therefore, these five proteins are considered as attractive targets for the development of antiviral agents against SARS CoV and mers2 cov Preliminary analysis of the genomic sequences from 2019-ncov showed that the four 2019-ncov enzymes had highly conserved catalytic sites, and had high sequence similarity with the corresponding SARS CoV and mers2 cov enzymes, so they may become anti-virus targets In addition, protein structure analysis suggests that in 2019 ncov, SARS CoV and mers2 CoV, the key drug binding pocket of viral enzyme is likely to be conservative Therefore, it is reasonable to consider the reuse of existing mers2 CoV and SARS CoV inhibitors to inhibit 2019 ncov Next, Dr Li and Dr clercq discussed the selected candidate drugs, focusing on the approved drugs or experimental drugs that have been tested in clinical trials of other diseases Table 1 provides a longer list of anti coronavirus drugs, including preclinical compounds that may be considered for screening antiviral drugs for 2019 ncov or as a starting point for optimizing them A potential candidate drug (1) virus targeting agent for reuse against 2019 ncov Approved nucleoside analogues (fabiravir and ribavirin) and experimental nucleoside analogues (ridcivir and galidivir) may have the potential to resist 2019 ncov Nucleoside analogues in the form of adenine or guanine derivatives target RNA dependent RNA polymerases and block the synthesis of viral RNA in various RNA viruses, including human coronaviruses Favipiravir, T-705) is a guanine analogue approved for influenza treatment, which can effectively inhibit RNA dependent RNA polymerase of RNA viruses such as influenza virus, Ebola virus, yellow fever virus, chikungunya virus, norovirus and enterovirus Recent studies also reported that it has anti-2019-ncov activity (EC50 = 61.88 μ m in Vero E6 cells) Scientists are recruiting 2019 ncov patients in randomized clinical trials to evaluate the efficacy of fabiravir combined with interferon - α (chictr2000029600) and fabiravir combined with baloxavir marboxil (chictr2000029544), an approved influenza virus inhibitor targeting cap dependent endonuclease Ribavirin, a guanine derivative approved for the treatment of HCV and RSV, has been evaluated in SARS CoV and mers cov patients, but its side effects such as anemia may be serious at high doses, and whether it has sufficient anti-2019-ncov efficacy is uncertain Remdesivir (gs-5734) is a aminophosphate prodrug derived from adenine Its chemical structure is similar to that of tenofovir, an approved HIV reverse transcriptase inhibitor Radcivir has broad-spectrum antiviral activity against RNA viruses such as mers CoV and SARS CoV in cell cultures and animal models, and has been tested in a clinical trial against Ebola virus A recent study reported that radcivir can inhibit 2019 ncov (EC50 = 0.77 μ m in Vero E6 cells), and a US 2019 ncov patient recovered from intravenous injection of radcivir in January 2020 Two phase III clinical trials initiated in early February 2020 were designed to evaluate the intravenous infusion of ridcivir (200 mg on day 1 and 100 mg on the following 9 days) in 2019-ncov patients (nct04252664 and nct04257656), with an estimated completion date of April 2020 Galidesivir (bcx4430) is an adenosine analogue originally developed for HCV infected people At present, it is in early clinical research to evaluate its safety and efficacy against yellow fever virus in healthy subjects It has shown antiviral activity against many RNA viruses including mers CoV and SARS CoV in preclinical research It is reported that the approved protease inhibitors, including disulfiram, lopinavir and ritonavir, have the activity of resisting mers CoV and SARS CoV Disulfiram is a drug approved for the treatment of alcohol dependence It has been reported that it can inhibit the papain like protease of mers CoV and SARS CoV in cell culture, but there is no clinical evidence Scientists have started clinical trials (such as chictr2000029539) to test HIV protease inhibitors such as lopinavir and ritonavir in 2019-ncov patients It was initially speculated that lopinavir and ritonavir could inhibit the 3-chymotrypsin like protease of mers CoV and SARS CoV, and in a non randomized open label trial, they seemed to be related to the improvement of clinical results in SARS CoV patients However, it is controversial whether HIV protease inhibitors can effectively inhibit the 3-chymotrypsin like protease and papain like protease of 2019 ncov HIV protease belongs to the aspartate protease family, and these two coronavirus proteases belong to the cysteine protease family In addition, HIV protease inhibitors were specially optimized to adapt to the C2 symmetry of the catalytic site of HIV protease dimer, but this C2 symmetry pocket does not exist in coronavirus protease If HIV protease inhibitors alter host pathways to indirectly interfere with coronavirus infection, their efficacy remains a problem Spike glycoprotein is also a promising target Griffithsin is a agglutinin derived from red algae, which can bind to oligosaccharides on the surface of various viral glycoproteins (including HIV glycoprotein 120 and SARS CoV spike glycoprotein) Graaff Sen has been tested as a gel or enema to prevent HIV in phase I clinical research However, when treating or preventing 2019-nCoV, we should re evaluate the efficacy and dosage of the spike glycoprotein inhibitor (2) Host targeting agent Pegylated interferon alfa-2a and alfa-2b, which have been approved for the treatment of HBV and HCV, may be used to stimulate the innate antiviral response of patients with 2019 ncov infection, and clinical trials involving interferon have been initiated, such as a clinical trial to test the approved anti HCV drug combination pegylated interferon ribavirin (chictr2000029387) However, it is not clear whether pegylated interferon and nucleoside compounds can cooperate against 2019 ncov Due to the existence of multiple adverse reactions associated with subcutaneous interferon therapy, their evaluation should be closely monitored and may require dose reduction or termination of treatment Small molecule reagents that have been approved for use in the treatment of other human diseases may modulate the virus host interaction of 2019-ncov As an approved immunomodulator, chloroquine has shown an inhibitory effect on 2019-ncov (EC50 = 1.13 μ m in Vero E6 cells) and is being evaluated in an open label clinical trial (chictr2000029609) Nitazoxanide, which has been approved for diarrhea treatment, can also inhibit 2019 ncov (EC50 = 2.12 μ m in Vero E6 cells) The antiviral efficacy of these small molecular reagents needs to be evaluated in clinical studies It is worth mentioning that although many attempts have been made in the past 50 years to develop host specific molecules to fight against the virus infection, only maraviroc has been approved by the US Food and Drug Administration (FDA) for HIV treatment In view of the understanding of the safety of existing antiviral drugs and their effectiveness in some cases for closely related coronaviruses, their reuse may be an important near-term strategy for 2019 ncov Phase III clinical trials have been initiated for readcivir, and many other trials are underway in China to test treatment options such as umifenovir hydrochloride, oseltamivir, and asc09f (Table 1) In addition, more than 50 existing mers CoV and / or SARS CoV inhibitors, such as gallidivir, protease inhibitor gc813 and compound 3k, helicase inhibitor ssya10-001 and nucleoside analogue pyrazofuran (Table 1), can be screened for their anti-2019-ncov activity through facilities with appropriate biological containment capability However, most of the reported EC50 and IC50 values of mers CoV and / or SARS CoV inhibitors are in the micromolar range, and their anti-2019-ncov activity may need to be further optimized before clinical evaluation With ongoing efforts to stop the spread of 2019 ncov around the world, Dr Li and Dr clercq hope that the epidemic may subside in a few months, just like the SARS ncov and mers ncov outbreaks Nevertheless, the outbreak highlights the urgent need for renewed efforts to develop broad-spectrum antiviral drugs against the coronavirus (Bio Valley bio Com) editor's note: given that the list of existing drugs listed in Table 1 is too long, details can be downloaded from the website (https://www.nature.com/magazine-assets/d41573-020-00016-0 / 17663286) Reference: Guangdi Li et al Theoretical options for the 2019 Novell corona (2019-ncov) Nature reviews drug discovery, 2020, DOI: 10.1038/d41573-020-00016-0