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1.
Viruses ; 14(6):1142, 2022.
Article in English | MDPI | ID: covidwho-1857421

ABSTRACT

Enterovirus infections can cause hand, foot, and mouth disease (HFDM), aseptic meningitis, encephalitis, myocarditis, and acute flaccid myelitis, leading to death of infants and young children. However, no specific antiviral drug is currently available for the treatment of this type of infection. The Unites States and United Kingdom health authorities recently approved a new antiviral drug, molnupiravir, for the treatment of COVID-19. In this study, we reported that molnupiravir (EIDD-2801) and its active form, EIDD-1931, have broad-spectrum anti-enterovirus potential. Our data showed that EIDD-1931 could significantly reduce the production of EV-A71 progeny virus and the expression of EV-A71 viral protein at non-cytotoxic concentrations. The results of the time-of-addition assay suggest that EIDD-1931 acts at the post-entry step, which is in accordance with its antiviral mechanism. The intraperitoneal administration of EIDD-1931 and EIDD-2801 protected 1-day-old ICR suckling mice from lethal EV-A71 challenge by reducing the viral load in various tissues of the infected mice. The pharmacokinetics analysis indicated that the plasma drug concentration overwhelmed the EC50 for enteroviruses, suggesting the clinical potential of molnupiravir against enteroviruses. Thus, molnupiravir along with its active form, EIDD-1931, may be a promising drug candidate against enterovirus infections.

5.
Virol Sin ; 35(6): 776-784, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-1217480

ABSTRACT

The recent outbreak of novel coronavirus pneumonia (COVID-19) caused by a new coronavirus has posed a great threat to public health. Identifying safe and effective antivirals is of urgent demand to cure the huge number of patients. Virus-encoded proteases are considered potential drug targets. The human immunodeficiency virus protease inhibitors (lopinavir/ritonavir) has been recommended in the global Solidarity Trial in March launched by World Health Organization. However, there is currently no experimental evidence to support or against its clinical use. We evaluated the antiviral efficacy of lopinavir/ritonavir along with other two viral protease inhibitors in vitro, and discussed the possible inhibitory mechanism in silico. The in vitro to in vivo extrapolation was carried out to assess whether lopinavir/ritonavir could be effective in clinical. Among the four tested compounds, lopinavir showed the best inhibitory effect against the novel coronavirus infection. However, further in vitro to in vivo extrapolation of pharmacokinetics suggested that lopinavir/ritonavir could not reach effective concentration under standard dosing regimen [marketed as Kaletra®, contained lopinavir/ritonavir (200 mg/50 mg) tablets, recommended dosage is 400 mg/10 mg (2 tablets) twice daily]. This research concluded that lopinavir/ritonavir should be stopped for clinical use due to the huge gap between in vitro IC50 and free plasma concentration. Nevertheless, the structure-activity relationship analysis of the four inhibitors provided further information for de novel design of future viral protease inhibitors of SARS-CoV-2.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Coronavirus 3C Proteases/antagonists & inhibitors , Lopinavir/pharmacology , Ritonavir/pharmacology , SARS-CoV-2/drug effects , SARS-CoV-2/enzymology , Viral Protease Inhibitors/pharmacology , Animals , Antiviral Agents/chemistry , COVID-19/blood , COVID-19/virology , Cell Line , Chlorocebus aethiops , Coronavirus 3C Proteases/chemistry , Coronavirus 3C Proteases/metabolism , Drug Combinations , Humans , Lopinavir/blood , Male , Molecular Docking Simulation , Ritonavir/blood , Vero Cells , Viral Protease Inhibitors/chemistry
6.
J Med Microbiol ; 70(3)2021 Mar.
Article in English | MEDLINE | ID: covidwho-1140049

ABSTRACT

In this work, we studied the profile of IgM and IgG antibody responses to SARS-CoV-2 in 32 patients with COVID-19 from day 1 to day 24. IgM remained measurable for a much shorter period than IgG, suggesting that IgG antibody may represent the primary immune response.


Subject(s)
Antibodies, Viral/blood , COVID-19/immunology , SARS-CoV-2/immunology , Adult , Aged , COVID-19/diagnosis , Coronavirus Nucleocapsid Proteins/immunology , Female , Humans , Immunoglobulin G/blood , Immunoglobulin M/blood , Kinetics , Male , Middle Aged , Phosphoproteins/immunology , RNA, Viral/analysis , SARS-CoV-2/genetics , SARS-CoV-2/isolation & purification , Spike Glycoprotein, Coronavirus/immunology
8.
EBioMedicine ; 62: 103125, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-938894

ABSTRACT

BACKGROUND: The pharmacokinetics and appropriate dose regimens of favipiravir are unknown in hospitalized influenza patients; such data are also needed to determine dosage selection for favipiravir trials in COVID-19. METHODS: In this dose-escalating study, favipiravir pharmacokinetics and tolerability were assessed in critically ill influenza patients. Participants received one of two dosing regimens; Japan licensed dose (1600 mg BID on day 1 and 600 mg BID on the following days) and the higher dose (1800 mg/800 mg BID) trialed in uncomplicated influenza. The primary pharmacokinetic endpoint was the proportion of patients with a minimum observed plasma trough concentration (Ctrough) ≥20 mg/L at all measured time points after the second dose. RESULTS: Sixteen patients were enrolled into the low dose group and 19 patients into the high dose group of the study. Favipiravir Ctrough decreased significantly over time in both groups (p <0.01). Relative to day 2 (48 hrs), concentrations were 91.7% and 90.3% lower in the 1600/600 mg group and 79.3% and 89.5% lower in the 1800/800 mg group at day 7 and 10, respectively. In contrast, oseltamivir concentrations did not change significantly over time. A 2-compartment disposition model with first-order absorption and elimination described the observed favipiravir concentration-time data well. Modeling demonstrated that less than 50% of patients achieved Ctrough ≥20 mg/L for >80% of the duration of treatment of the two dose regimens evaluated (18.8% and 42.1% of patients for low and high dose regimen, respectively). Increasing the favipravir dosage predicted a higher proportion of patients reaching this threshold of 20 mg/L, suggesting that dosing regimens of ≥3600/2600 mg might be required for adequate concentrations. The two dosing regimens were well-tolerated in critical ill patients with influenza. CONCLUSION: The two dosing regimens proposed for uncomplicated influenza did not achieve our pre-defined treatment threshold.


Subject(s)
Amides , Influenza, Human/drug therapy , Oseltamivir , Pyrazines , Aged , Amides/administration & dosage , Amides/pharmacokinetics , Drug Therapy, Combination , Female , Humans , Influenza, Human/blood , Male , Middle Aged , Oseltamivir/administration & dosage , Oseltamivir/pharmacokinetics , Pyrazines/administration & dosage , Pyrazines/pharmacokinetics , Severity of Illness Index
9.
Signal Transduct Target Ther ; 5(1): 240, 2020 10 15.
Article in English | MEDLINE | ID: covidwho-872677

ABSTRACT

The COVID-19 pandemic has emerged as a global health emergency due to its association with severe pneumonia and relative high mortality. However, the molecular characteristics and pathological features underlying COVID-19 pneumonia remain largely unknown. To characterize molecular mechanisms underlying COVID-19 pathogenesis in the lung tissue using a proteomic approach, fresh lung tissues were obtained from newly deceased patients with COVID-19 pneumonia. After virus inactivation, a quantitative proteomic approach combined with bioinformatics analysis was used to detect proteomic changes in the SARS-CoV-2-infected lung tissues. We identified significant differentially expressed proteins involved in a variety of fundamental biological processes including cellular metabolism, blood coagulation, immune response, angiogenesis, and cell microenvironment regulation. Several inflammatory factors were upregulated, which was possibly caused by the activation of NF-κB signaling. Extensive dysregulation of the lung proteome in response to SARS-CoV-2 infection was discovered. Our results systematically outlined the molecular pathological features in terms of the lung response to SARS-CoV-2 infection, and provided the scientific basis for the therapeutic target that is urgently needed to control the COVID-19 pandemic.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/genetics , Lung Injury/genetics , Pneumonia, Viral/genetics , Proteome/genetics , Proteomics/methods , Severe Acute Respiratory Syndrome/genetics , Aged , Autopsy , COVID-19 , Coronavirus Infections/metabolism , Coronavirus Infections/pathology , Coronavirus Infections/virology , Cytokines/genetics , Cytokines/metabolism , Female , Gene Expression Profiling , Gene Expression Regulation , Gene Ontology , Humans , Lung/metabolism , Lung/pathology , Lung/virology , Lung Injury/metabolism , Lung Injury/pathology , Lung Injury/virology , Male , Metabolic Networks and Pathways , Molecular Sequence Annotation , NF-kappa B/genetics , NF-kappa B/metabolism , Pandemics , Pneumonia, Viral/metabolism , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , Proteome/metabolism , SARS-CoV-2 , Severe Acute Respiratory Syndrome/metabolism , Severe Acute Respiratory Syndrome/pathology , Severe Acute Respiratory Syndrome/virology , Severity of Illness Index , Signal Transduction
11.
ACS Infect Dis ; 6(9): 2524-2531, 2020 09 11.
Article in English | MEDLINE | ID: covidwho-695395

ABSTRACT

The discovery of novel drug candidates with anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) potential is critical for the control of the global COVID-19 pandemic. Artemisinin, an old antimalarial drug derived from Chinese herbs, has saved millions of lives. Artemisinins are a cluster of artemisinin-related drugs developed for the treatment of malaria and have been reported to have multiple pharmacological activities, including anticancer, antiviral, and immune modulation. Considering the reported broad-spectrum antiviral potential of artemisinins, researchers are interested in whether they could be used to combat COVID-19. We systematically evaluated the anti-SARS-CoV-2 activities of nine artemisinin-related compounds in vitro and carried out a time-of-drug-addition assay to explore their antiviral mode of action. Finally, a pharmacokinetic prediction model was established to predict the therapeutic potential of selected compounds against COVID-19. Arteannuin B showed the highest anti-SARS-CoV-2 potential with an EC50 of 10.28 ± 1.12 µM. Artesunate and dihydroartemisinin showed similar EC50 values of 12.98 ± 5.30 µM and 13.31 ± 1.24 µM, respectively, which could be clinically achieved in plasma after intravenous administration. Interestingly, although an EC50 of 23.17 ± 3.22 µM was not prominent among the tested compounds, lumefantrine showed therapeutic promise due to high plasma and lung drug concentrations after multiple dosing. Further mode of action analysis revealed that arteannuin B and lumefantrine acted at the post-entry step of SARS-CoV-2 infection. This research highlights the anti-SARS-CoV-2 potential of artemisinins and provides leading candidates for anti-SARS-CoV-2 drug research and development.


Subject(s)
Antiviral Agents/pharmacology , Artemisinins/pharmacology , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Pneumonia, Viral/drug therapy , Pneumonia, Viral/virology , Animals , Antimalarials/pharmacology , COVID-19 , Chlorocebus aethiops , Drug Discovery , Drug Repositioning , Drugs, Chinese Herbal/pharmacology , Pandemics , SARS-CoV-2 , Vero Cells
12.
Engineering (Beijing) ; 6(10): 1192-1198, 2020 Oct.
Article in English | MEDLINE | ID: covidwho-9104

ABSTRACT

There is currently an outbreak of respiratory disease caused by a novel coronavirus. The virus has been named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the disease it causes has been named coronavirus disease 2019 (COVID-19). More than 16% of patients developed acute respiratory distress syndrome, and the fatality ratio was 1%-2%. No specific treatment has been reported. Herein, we examined the effects of favipiravir (FPV) versus lopinavir (LPV)/ritonavir (RTV) for the treatment of COVID-19. Patients with laboratory-confirmed COVID-19 who received oral FPV (Day 1: 1600 mg twice daily; Days 2-14: 600 mg twice daily) plus interferon (IFN)-α by aerosol inhalation (5 million international unit (IU) twice daily) were included in the FPV arm of this study, whereas patients who were treated with LPV/RTV (Days 1-14: 400 mg/100 mg twice daily) plus IFN-α by aerosol inhalation (5 million IU twice daily) were included in the control arm. Changes in chest computed tomography (CT), viral clearance, and drug safety were compared between the two groups. For the 35 patients enrolled in the FPV arm and the 45 patients in the control arm, all baseline characteristics were comparable between the two arms. A shorter viral clearance median time was found for the FPV arm versus the control arm (4 d (interquartile range (IQR): 2.5-9) versus 11 d (IQR: 8-13), P < 0.001). The FPV arm also showed significant improvement in chest CT compared with the control arm, with an improvement rate of 91.43% versus 62.22% (P = 0.004). After adjustment for potential confounders, the FPV arm also showed a significantly higher improvement rate in chest CT. Multivariable Cox regression showed that FPV was independently associated with faster viral clearance. In addition, fewer adverse events were found in the FPV arm than in the control arm. In this open-label before-after controlled study, FPV showed better therapeutic responses on COVID-19 in terms of disease progression and viral clearance. These preliminary clinical results provide useful information of treatments for SARS-CoV-2 infection.

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