Study on the combination of remdesivir and mers cov

The novel coronavirus (2019-nCoV) epidemic in Wuhan has spread to dozens of countries around the world since December 2019, and tens of thousands of people have been confirmed to be infected by Zhang Jian For novel coronavirus pneumonia, there is no effective antiviral therapy except symptomatic treatment The novel coronavirus infection pneumonia diagnosis and treatment plan (trial version fifth) recommends that antiviral treatment can be tested with alpha interferon (broad-spectrum antiviral drugs) inhalation, Lo Pinave (Lopinavir, LPV) / ritonavir (Ritonavir, RTV) (HIV protease inhibitor), or add Leigh Bhave Lin (broad-spectrum antiviral drugs) A novel coronavirus novel coronavirus pneumonia case with rapidly improved symptoms after intravenous injection of Reed Remdesivir (RDV) was reported in the new England Journal of medicine in January 31, 2020 It brings new hope for the treatment of new coronavirus pneumonia Novel coronavirus (2019-nCoV) pneumonia was treated by Reed and III in phase II clinical trials Scientists from Gilead and the University of North Carolina, Chapel Hill, have used ridcivir to study the treatment strategy of the Middle East respiratory syndrome coronavirus (mers COV), and compared the efficacy of RDV, LPV, RTV and IFNb on the Middle East respiratory syndrome coronavirus (mers COV), which is on 2019 ncov The strategy of clinical use is of great significance Gs-5734 is an antiviral drug initially developed by Gilead science company for the treatment of Ebola virus infection, which is in phase III clinical research stage Subsequently, it was found that it has broad-spectrum antiviral activity, and has antiviral activity against respiratory syncytial virus (RSV), juninvirus, lassafer virus, mers CoV, SARS and Nipah virus in vitro Radcivir is a new type of adenosine analogue monophosphate amide prodrug It can be transformed into the pharmacological active form of nucleoside triphosphate (NTP) in cells, which can inhibit RNA polymerase of virus and nucleic acid synthesis of virus Middle East respiratory syndrome (mers) is a serious respiratory disease caused by mers cov Its main symptoms include fever, cough, dyspnea, diarrhea, nausea, vomiting and other digestive symptoms, which may lead to severe complications such as pneumonia and renal failure Since 2012, mers-cov has infected more than 2468 people and killed more than 851 people worldwide Because new viral diseases often lack or have few effective treatment options, it is necessary to empirically give patients drugs designed and approved for other diseases based on limited clinical or laboratory data At present, there is only one clinical trial to evaluate the feasibility, efficacy and safety of LPV / rtv-ifnb in hospitalized patients infected with mers cov No drug has been approved for the treatment of mers cov infection The researchers tried to study the effect of RDV on mers cov in vitro and in vivo, and compared it with LPV / rtv-ifnb in clinical trials First, the researchers constructed a recombinant mers cov (mers nluc) expressing luciferase reporting system to evaluate the antiviral activity of the drug in vitro In Calu-3 cells infected with mers nluc, RDV and IFNb could inhibit the replication of mers CoV, which was superior to LPV and RTV RTV did not significantly enhance the antiviral activity of LPV When LPV / RTV is in clinical relevant concentration, the in vitro antiviral activity of LPV / rtv-ifnb is mainly produced by IFNb Then, the researchers prepared a transgenic mouse model (ces1c - / - hdp4) expressing human mers cov receptor (hdp4) and knocking out carboxylesterase 1C (ces1c), in order to better simulate the pharmacokinetics and exposure characteristics of RDV in human body In the ces1c - / - hdp4 mouse model, the researchers evaluated the efficacy of prophylactic and therapeutic administration, respectively Prophylactic administration of RDV can reduce weight loss, pulmonary hemorrhage, mers cov replication and acute lung injury in mice The preventive administration of LPV / rtv-ifnb or IFNb alone failed to prevent the weight loss of mice, and the mice with IFNb alone lost more weight On the sixth day after injection, RDV could significantly reduce the titer of pulmonary virus (> 3log), while low dose LPV / rtv-ifnb only reduced the titer by about 4 times, while high dose group and IFNb alone had no significant effect on the titer Only RDV prophylactic administration can significantly improve lung function, while IFNb alone can significantly worsen lung function Therapeutic administration of RDV can reduce weight loss, pulmonary hemorrhage and mers cov replication in mice, but the degree of clinical benefit depends on the dose of the virus and the time of administration RDV can significantly improve the lung function indexes such as mid expiratory flow rate (EF50), airway stenosis index (Penh) and peak expiratory time ratio (rpef), and reduce the symptoms of acute lung injury Although low and high dose of LPV / rtv-ifnb did not reduce weight loss, pulmonary hemorrhage and mers cov replication in mice, low dose of LPV / rtv-ifnb could improve lung function in mice LPV / rtv-ifnb has no effect on acute lung injury in mice In conclusion, compared with LPV / rtv-ifnb, RDV has stronger anti mers cov activity in vitro and in vivo This study provides in vivo evidence for the use of RDV in the treatment of mers cov infection For all human coronavirus infections, there is no FDA approved treatment drugs, most of which are super indications antiviral drugs and immunomodulators There is an urgent need to develop broad-spectrum antiviral drugs against known epidemics and zoonoses in order to reduce the prevalence of the disease and future outbreaks In this paper, the author analyzes the characteristics of, et al., Remdesivir (GS-5734) protects African green monkeysfrom Nipah virus challenge Sci Transl Med, 2019 11(494): eaau9242 4.Brown, A.J., et al., Broad spectrum antiviral remdesivir inhibits humanendemic and zoonotic deltacoronaviruses with a highly divergent RNA dependentRNA polymerase Antiviral Res, 2019 169: 104541 5.Siegel, D., et al., Discovery and Synthesis of a PhosphoramidateProdrug of a Pyrrolo[2,1-f][triazin-4-amino] Adenine C-Nucleoside (GS-5734) forthe Treatment of Ebola and Emerging Viruses J Med Chem, 2017 60(5):1648-1661 6.Sheahan, T.P., et al., Broad-spectrum antiviral GS-5734 inhibits bothepidemic and zoonotic coronaviruses Sci Transl Med, 2017.9 (396): eaal3653 7 Lo, M.K., et al., gs-5734 and its parent nucleus anlog inhibitfilo -, pneumo -, and paramyxoviruses SCI Rep, 2017.7: 43395 8 Warren, T.K., et al., theoretical efficiency of the small motorcycle gs-5734 against Ebola virus in rhesus monkeys Nature, 2016.531 (7594): 381-5