LitCovid-sentences  

PMC:7127386 / 1495-18678 JSONTXT 14 Projects

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Id Subject Object Predicate Lexical cue
T14 0-228 Sentence denotes Within three months of the first identification of SARS-CoV-2 virus in Wuhan, Hubei Province, China, the world is facing an escalating pandemic that will have significant impacts on global health systems and economy (WHO, 2019).
T15 229-506 Sentence denotes Infection with the novel SARS-CoV-2 virus may lead to a wide range of clinical presentations from asymptomatic infection in 1% of laboratory confirmed cases to mild, severe, and critical infections in 81%, 14%, and 5% of symptomatic cases, respectively (Wu and McGoogan, 2020).
T16 507-709 Sentence denotes The estimated symptomatic case-fatality risk (sCFR) among cases in Wuhan was 1.4%, and those aged above 59 were 5.1 times more likely to die from infection than those aged 30–59 years (Wu et al., 2020).
T17 710-939 Sentence denotes With an estimated basic reproductive number of 2.2 (95% CI, 1.4–3.9) (Li et al., 2020), the virus will continue to spread and infect 55% of the global population over time if no effective vaccine is developed (Fine et al., 2011).
T18 940-1060 Sentence denotes There is currently no effective antiviral compound licensed for the treatment against human coronaviruses or SARS-CoV-2.
T19 1061-1227 Sentence denotes The SARS-CoV-2 virus shared 79.5% genetic homology to the SARS-CoV and both are descendants of bat coronaviruses within the Betacoronavirus genus (Zhou et al., 2020).
T20 1228-1458 Sentence denotes Antiviral compounds previously reported to show effect against SARS-CoV or other coronaviruses may be effective against SARS-CoV-2 (Chu et al., 2004; de Wilde et al., 2014; Dyall et al., 2014; Shen et al., 2019; Cao et al., 2015).
T21 1459-1759 Sentence denotes In addition, remdesivir (GS-5734), a prodrug of adenosine analog with a broad-spectrum antiviral activity against filoviruses, paramyxoviruses, and coronaviruses (Brown et al., 2019; Sheahan et al., 2017; de Wit et al., 2020), was recently confirmed to inhibit 2019-nCoV in vitro (Wang et al., 2020).
T22 1760-2130 Sentence denotes According to the 7th edition of the novel coronavirus diagnosis and treatment plan issued by the National Health Commission of the People's Republic of China, options for antiviral therapy include aerosolized α-interferon, lopinavir/ritonavir, ribavirin in combination with lopinavir/ritonavir, chloroquine phosphate, or Arbidol (China National Health Commission, 2020).
T23 2131-2478 Sentence denotes Ongoing clinical trials are evaluating the efficacy of remdesivir, and various HIV-protease inhibitors (lopinavir/ritonavir, ASC09/ritonavir, darunavir), reverse transcriptase inhibitor (Azvudine), anti-influenza compounds, interferon alfa-2b, or monoclonal antibody targeting PD-1 (Camrelizumab) or IL-6 (Tocilizumab) (Chinese Clinical Trial Re).
T24 2479-2793 Sentence denotes We evaluated the anti-SARS-CoV-2 effect of compounds that have been under development or already approved for other clinical applications; some compounds were previously reported to inhibit coronavirus replication in vitro, and some are evaluated in clinical trials in patients with coronavirus disease (COVID-19).
T25 2794-2987 Sentence denotes SARS-CoV-2 virus, BetaCoV/Hong Kong/VM20001061/2020, was isolated from the nasopharynx aspirate and throat swab of a confirmed COVID-19 patient in Hong Kong using Vero E6 cells (ATCC CRL-1586).
T26 2988-3227 Sentence denotes Stock virus (107.25 TCID50/mL) was prepared after three serial passages in Vero E6 cells in infection media (DMEM supplemented with 4.5 g/L D-glucose, 100 mg/L sodium pyruvate, 2% FBS, 100,000 U/L Penicillin-Streptomycin, and 25 mM HEPES).
T27 3228-3698 Sentence denotes Compounds were sourced from MedChemExpress and Sigma-Aldrich and the stocks were prepared with DMSO (50 mM remdesivir, 100 mM favipiravir, 10 mM R-1479, 10 mM tenofovir, 10 mM fludarabine phosphate, 10 mM baloxavir, 10 mM chlorpromazine hydrochloride, 5 mM dalbavancin hydrochloride, 10 mM homoharringtonine, 10 mM lopinavir, 10 mM ritonavir) or with water (5 mM emetine dihydrochloride, 10 mM galidesivir hydrochloride, 50 mM ribavirin, 2.5 mM oritavancin diphosphate).
T28 3699-3762 Sentence denotes Oseltamivir carboxylate (10 mM in water) was provided by Roche.
T29 3763-3943 Sentence denotes To evaluate the effect of compounds in vitro, Vero E6 cells were pre-treated with compounds diluted in infection media for 1 h prior to infection by SARS-CoV-2 virus at MOI = 0.02.
T30 3944-4037 Sentence denotes Antiviral compounds were maintained with the virus inoculum during the 2-h incubation period.
T31 4038-4159 Sentence denotes The inoculum was removed after incubation, and the cells were overlaid with infection media containing diluted compounds.
T32 4160-4383 Sentence denotes After 48 h incubation at 37 °C, supernatants were collected to quantify viral loads by TCID50 assay or quantitative real-time RT-PCR (TaqMan™ Fast Virus 1-Step Master Mix) following the methods described (Chu et al., 2020).
T33 4384-4580 Sentence denotes Four-parameter logistic regression (GraphPad Prism) was used to fit the dose-response curves and determined the 50% effective concentrations (EC50) of the compounds that inhibit viral replication.
T34 4581-4714 Sentence denotes Cytotoxicty of selected compounds was evaluated in Vero E6 cells using the CellTiter-Glo® Luminescent Cell Viability Assay (Promega).
T35 4715-4915 Sentence denotes Among the 16 compounds we tested, remdesivir, lopinavir, homoharringtonine, and emetine dihydrochloride were found to inhibit SARS-CoV-2 replication in Vero E6 cells with EC50 under 100 μM (Table 1 ).
T36 4916-5178 Sentence denotes Importantly, we observed that some of the compounds currently undergoing clinical trials such as ribavirin, favipiravir, oseltamivir, or baloxavir showed no apparent antiviral effect against the SARS-CoV-2 virus in vitro at concentrations under 100 μM (Table 1).
T37 5179-5411 Sentence denotes Remdesivir is a 1′-cyano-substituted adenosine analogue that has been shown to inhibit human coronaviruses (hCoV-OC43 and hCoV-229E) SARS-CoV, MERS-CoV, and SARS-CoV-2 (Brown et al., 2019; Sheahan et al., 2017; de Wit et al., 2020).
T38 5412-5480 Sentence denotes It is currently evaluated in phase 4 clinical trials for SARS-CoV-2.
T39 5481-5681 Sentence denotes A recent study fitted viral load in linear scale (eg. the percentage of inhibition) under increasing concentrations of remdesivir reported EC50 against SARS-CoV-2 virus at 0.77 μM (Wang et al., 2020).
T40 5682-5896 Sentence denotes We fitted viral load in logarithm scale (log10TCID50/mL and log10 viral RNA copies/mL) under increasing concentration of remdesivir and determined EC50 at 23.15 μM and 26.90 μM, respectively (Fig. 1 A and Table 1).
T41 5897-6088 Sentence denotes Two mutations (F476L and V553L) in the RNA-dependent RNA polymerase nsp12 of a murine hepatitis virus have been previously reported to confer resistance to remdesivir (Agostini et al., 2018).
T42 6089-6310 Sentence denotes Due to insertions and deletions in nsp12, these two conserved residues are mapped at F480 and V557 in the SARS-CoV-2 isolate (GISAID# EPI_ISL_412028) used for the experiments, which should remain sensitive for remdesivir.
T43 6311-6502 Sentence denotes Other adenosine analogues (galidesivir, tenofovor, or fludarabine phosphate) or nucleoside analogues (favipiravir, ribavirin, R-1479) did not inhibit viral replication under 100 μM (Table 1).
T44 6503-6663 Sentence denotes However, nucleoside analogues require metabolic activation into their triphosphate forms by host cellular nucleoside kinases, which may differ among cell types.
T45 6664-6813 Sentence denotes Further evaluation of the effect of nucleoside analogues in primary human airway epithelial cells would facilitate the interpretation of the results.
T46 6814-6893 Sentence denotes Table 1 Antiviral activity of 16 compounds against SARS-CoV-2 in Vero E6 cells.
T47 6894-6941 Sentence denotes Compounds Inhibition of SARS-CoV-2 in vitro, μM
T48 6942-6987 Sentence denotes Name Bioactivity Clinical application CAS No.
T49 6988-7087 Sentence denotes CC50, μMa CPE inhibitionb Reduction in infectious virusc (EC50) Reduction in viral RNA copyd (EC50)
T50 7088-7202 Sentence denotes Remdesivir adenosine analogue Phase 4 trials for treatment of Ebola or SARS-CoV-2 1809249-37-3 >100 25 23.15 26.90
T51 7203-7327 Sentence denotes Favipiravir guanineanalogue Approved in Japan and China for treatment of influenza infection 259793-96-9 >100 >100 >100 >100
T52 7328-7446 Sentence denotes Ribavirin guanosine analogue FDA approved for treatment of chronic hepatitis C infection 36791-04-5 >100 500 >500 >500
T53 7447-7555 Sentence denotes Galidesivir adenosine analogue Phase 2 trial for yellow fever virus infection 222631-44-9 >100 100 >100 >100
T54 7556-7660 Sentence denotes R-1479 cytidineanalogue Phase 2 trial for treatment of dengue virus infection 478182-28-4 >100 >100 N.D.
T55 7661-7665 Sentence denotes N.D.
T56 7666-7765 Sentence denotes Tenofovor adenosine analogue FDA approved for treatment of HIV-1 and HBV 147127-20-6 >100 >100 N.D.
T57 7766-7770 Sentence denotes N.D.
T58 7771-7903 Sentence denotes Fludarabine phosphate adenosine analogue FDA approved for treatment of B-cell chronic lymphocytic leukemia 75607-67-9 >100 >100 N.D.
T59 7904-7908 Sentence denotes N.D.
T60 7909-8046 Sentence denotes Lopinavir protease inhibitor FDA approved for treatment of HIV-1 infection in combination with ritonavir 192725-17-0 49.75 25 26.63 26.10
T61 8047-8202 Sentence denotes Ritonavir protease inhibitor FDA approved for treatment of HIV-1 infection in combination with other antiretroviral agents 155213-67-5 48.91 >100 >100 >100
T62 8203-8320 Sentence denotes Emetine hydrochloride anti-protozoal Approved in China for severe invasive amoebiasis 316-42-7 56.46 1.5625 0.46 0.50
T63 8321-8458 Sentence denotes Oritavancin diphosphate antibiotics FDA approved treatment for skin infection caused by Gram positive bacteria 192564-14-0 N.D. >100 N.D.
T64 8459-8463 Sentence denotes N.D.
T65 8464-8604 Sentence denotes Dalbavancin hydrochloride antibiotics FDA approved treatment for skin infection caused by Gram positive bacteria 2227366-51-8 N.D. >100 N.D.
T66 8605-8609 Sentence denotes N.D.
T67 8610-8724 Sentence denotes Homoharringtonine anti-cancer FDA approved treatment for chronic myeloid leukemia 26833-87-4 59.75 3.125 2.55 2.14
T68 8725-8862 Sentence denotes Oseltamivir carboxylate antiviral, neuraminidase inhibitor FDA approved treatment for influenza infection 187227-45-8 >100 >100 >100 >100
T69 8863-8992 Sentence denotes Baloxivir acid antiviral, endonuclease inhibitor FDA approved treatment for influenza infection 1985605-59-1 85.90 >100 >100 >100
T70 8993-9125 Sentence denotes Chlorpromazine hydrochloride antagonist for post-synaptic receptors FDA approved treatment for schizophrenia 69-09-0 21.29 >100 N.D.
T71 9126-9130 Sentence denotes N.D.
T72 9131-9135 Sentence denotes N.D.
T73 9136-9151 Sentence denotes Not determined.
T74 9152-9311 Sentence denotes a CC50 was determined with serially-diluted compounds in Vero E6 cells at 48 h post-incubation using CellTiter-Glow Luminescent Cell Viability Assay (Promega).
T75 9312-9421 Sentence denotes b Compounds were serially 2-fold or 4-fold diluted from 100 μM, except ribavirin which was started at 500 μM.
T76 9422-9569 Sentence denotes Cytopathic effects (CPE) of SARS-CoV-2 virus in Vero E6 cells under increasing concentration of the compounds were observed at 48 h post-infection.
T77 9570-9706 Sentence denotes The lowest concentration of the compound with 100% CPE inhibition (eg. exhibiting comparable CPE of non-infected controls) was recorded.
T78 9707-9814 Sentence denotes c EC50 determined by infectious virus yield in culture supernatant at 48h post-infection (log10 TCID50/mL).
T79 9815-9926 Sentence denotes d EC50 determined by viral RNA copy numbers in culture supernatant at 48h post-infection (log10 RNA copies/mL).
T80 9927-10073 Sentence denotes Fig. 1 Antiviral activity of remdesivir (A), lopinavir (B), homorringtonine (C) and emetine dihydrochloride (D) against SARS-CoV-2 virus in vitro.
T81 10074-10291 Sentence denotes Infectious viral loads (log10TCID50/mL left Y axis) and viability (normalized to the ATP level of the Vero E6 cells incubated with infection media) under increasing concentrations of the antiviral compounds are shown.
T82 10292-10375 Sentence denotes Lopinavir in combination with ritonavir are FDA approved HIV-1 protease inhibitors.
T83 10376-10486 Sentence denotes Lopinavir was more potent in inhibiting HIV-1 than ritonavir in vitro but showed poor bioavailability in vivo.
T84 10487-10625 Sentence denotes Ritonavir inhibits not only HIV-1 protease but also the host's cytochrome P450 3A4 enzyme that metabolizes lopinavir (Kempf et al., 1997).
T85 10626-10727 Sentence denotes Lopinavir/ritonavir in combination prolongs bioavailability of lopinavir in vivo (Sham et al., 1998).
T86 10728-10898 Sentence denotes Lopinavir but not ritonavir showed antiviral effect against SARS-CoV, MERS-CoV, and hCoV-229E in vitro, with mean EC50 ranged from 6.6 to 17.1 μM (de Wilde et al., 2014).
T87 10899-11035 Sentence denotes Lopinavir/ritonavir in combination with ribavirin were used previously to treat SARS-CoV patients under a non-randomized clinical trial.
T88 11036-11241 Sentence denotes Less SARS patients developed into ARDS or death after receiving the combination of lopinavir/ritonavir with ribavirin than historical controls who received ribavirin and corticosteroids (Chu et al., 2004).
T89 11242-11378 Sentence denotes Efficacy of lopinavir/ritonavir with or without ribavirin is currently evaluated in SARS-CoV-2 patients under randomized control trials.
T90 11379-11543 Sentence denotes In agreement with previous reports, we observed antiviral effect of lopinavir (EC50 at 26.1 μM) but not ritonavir against SARS-CoV-2 in vitro (Fig. 1B and Table 1).
T91 11544-11795 Sentence denotes HIV-1 patients treated with 400 mg of lopinavir and 100 mg of ritonavir twice daily may reach the minimal lopinavir serum concentration at 9.4 μM (IQR 7.2–12.1 μM), which is below the EC50 against SARS-CoV-2 virus in vitro (Lopez-Cortes et al., 2013).
T92 11796-12000 Sentence denotes Currently, lopinavir/ritonavir at 400mg/100 mg twice daily with or without ribavirin are part of the recommended treatment for managing COVID-19 patients in China (China National Health Commission, 2020).
T93 12001-12302 Sentence denotes A recent randomized control trial reported no significant benefit of lopinavir-ritonavir in hospitalized SARS-CoV-2 patients than standard care, as the time to clinical improvement, mortality at 28 days, and viral loads at various time points were comparable between the two groups (Cao et al., 2020).
T94 12303-12472 Sentence denotes Combinational therapy of lopinavir with the other effective compounds against SARS-CoV-2 virus may increase synergy and reduce the inhibitory concentration of lopinavir.
T95 12473-12546 Sentence denotes Homoharringtonine is a plant alkaloid derived from Cephalotoxus fortunei.
T96 12547-12801 Sentence denotes It exhibits anti-tumor activity by binding to the ribosomal A site to inhibit protein translation, leading to rapid loss of short-lived proteins including Mcl-1 and c-Myc that promote the survival of leukemia cells (Dong et al., 2018; Lu and Wang, 2014).
T97 12802-12920 Sentence denotes Omacetaxine, a semi-synthetic form of homoharringtonine, is approved by FDA for treatment of chronic myeloid leukemia.
T98 12921-13329 Sentence denotes Homoharringtonine has also been reported to exhibit potent anti-viral activity against herpesviruses (varicella-zoster virus, herpes simplex virus-1, pseudorabies virus), coronaviruses (porcine epidemic diarrhea virus and murine hepatitis virus), rhabdoviruses (VSV and rabies virus), and other viruses (hepatitis B virus, Newcastle disease virus, and echovirus 1) (Dong et al., 2018; Andersen et al., 2019).
T99 13330-13429 Sentence denotes Here, we observed homoharringtonine inhibits SARS-CoV-2 with EC50 at 2.10 μM (Fig. 1C and Table 1).
T100 13430-13767 Sentence denotes Previous pharmacokinetic study showed that patients treated with 1.25 mg/m2 omacetaxine every 12 h by subcutaneous injection may reach the maximal plasma concentration at 25.1 ng/mL (0.046 μM) and 36.2 ng/mL (0.066 μM) on days 1 and 11, respectively (Nemunaitis et al., 2013), which were below the EC50 against SARS-CoV-2 virus in vitro.
T101 13768-14000 Sentence denotes Emetine is a protein synthesis inhibitor that was used as anti-protozoan approved for treatment of ameobiasis; it also inhibits malaria by binding to the ribosomal E site of Plasmodium falciparum (Grollman, 1966; Wong et al., 2014).
T102 14001-14091 Sentence denotes However, its potential cardiotoxicity has restricted its clinical use in the recent years.
T103 14092-14593 Sentence denotes It was found to process antiviral activity against a broad range of RNA and DNA viruses, including Zika virus, Ebolavirus, Cytomegalovirus, rabies virus, HIV-1, echovirus 1, buffalo poxvirus, bovine herpesvirus 1, peste des petits ruminants virus, Newcastle disease virus, herpes simplex virus-2, metapneumovirus, Rift Valley fever virus, and influenza (Andersen et al., 2019; Chaves Valadao et al., 2015; Khandelwal et al., 2017; MacGibeny et al., 2018; Mukhopadhyay et al., 2016; Yang et al., 2018).
T104 14594-14779 Sentence denotes Emetine was also identified to inhibit hCoV-OC43, hCoV-NL43, SARS-CoV, MERS-CoV, and MHV-A59 in vitro with EC50 reported at low micromolar range (Dyall et al., 2014; Shen et al., 2019).
T105 14780-14892 Sentence denotes We observed emetine at around 0.5 μM may effectively inhibit SARS-CoV-2 virus replication (Fig. 1D and Table 1).
T106 14893-15058 Sentence denotes The therapeutic plasma concentration of emetine may reach 0.075 μg/mL (0.156 μM) (Regenthal et al., 1999), which is below the EC50 against SARS-CoV-2 virus in vitro.
T107 15059-15138 Sentence denotes The toxic plasma concentration is 0.5 μg/mL (1.04 μM) (Regenthal et al., 1999).
T108 15139-15324 Sentence denotes To reduce the effective concentration of individual compound below the maximal therapeutic plasma concentration, we explored the combinational effect of remdesivir and emetine in vitro.
T109 15325-15475 Sentence denotes Drug interaction was evaluated using the checkerboard assay with serially 2-fold diluted remdesivir (0–50 μM) and emetine (0–0.781 μM) in combination.
T110 15476-15630 Sentence denotes Remdesivir at 6.25 μM in combination with emetine at 0.195 μM may achieve 64.9% inhibition of viral yield, which can be further tested in vivo (Fig. 2 A).
T111 15631-15815 Sentence denotes The Loewe additive model and the Bliss independent model (Malyutina et al., 2019) were used to analyse the interaction of the two compounds using SynergyFinder (Ianevski et al., 2017).
T112 15816-15949 Sentence denotes Remdesivir and emetine in combination yielded a Loewe synergy score of 0.306 (Fig. 2B) and a Bliss synergy score of 20.234 (Fig. 2C).
T113 15950-16170 Sentence denotes Fig. 2 Combinational effect of remdesivir and emetine dihydrochloride against SARS-CoV-2 virus in vitro. (A) Dose response matrix of serially 2-fold diluted remdesivir (0–50 μM) and emetine (0–0.781 μM) in Vero E6 cells.
T114 16171-16635 Sentence denotes The percentage of viral inhibition was normalized based on viral load in logarithm scale (log10RNA copies/mL), using the maximal viral RNA copies with no drug controls as 0% inhibition and the minimal RNA copies determined at 50 μM remdesivir as references. (B) The three-dimensional interaction landscapes of remdesivir and emetine were generated by SynergyFinder (Ianevski et al., 2017) based on (B) the Loewe additive model and (C) the Bliss independence model.
T115 16636-16726 Sentence denotes Red colour indicates synergy while the green colour indicates antagonism of the two drugs.
T116 16727-16867 Sentence denotes We confirm the antiviral activity of four compounds that have been reported to inhibit other coronavirus or SARS-CoV-2 replication in vitro.
T117 16868-17032 Sentence denotes Our results suggest that combinational therapy may help to reduce the effective concentration against SARS-CoV-2 under the maximal therapeutic plasma concentration.
T118 17033-17183 Sentence denotes There is an urgent research need to identify optimal dose combination of effective compounds against the SARS-CoV-2 virus for better clinical benefit.