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1.
Cell ; 2020.
Article | WHO COVID | ID: covidwho-785287

ABSTRACT

SUMMARY The emergence of SARS-CoV-2 led to pandemic spread of coronavirus disease 2019 (COVID-19), manifesting with respiratory symptoms and multi-organ dysfunction Detailed characterization of virus-neutralizing antibodies and target epitopes is needed to understand COVID-19 pathophysiology and guide immunization strategies Among 598 human monoclonal antibodies (mAbs) from ten COVID-19 patients, we identified 40 strongly neutralizing mAbs The most potent mAb CV07-209 neutralized authentic SARS-CoV-2 with IC50 of 3 1 ng/ml Crystal structures of two mAbs in complex with the SARS-CoV-2 receptor-binding domain at 2 55 and 2 70 Å revealed a direct block of ACE2 attachment Interestingly, some of the near-germline SARS-CoV-2 neutralizing mAbs reacted with mammalian self-antigens Prophylactic and therapeutic application of CV07-209 protected hamsters from SARS-CoV-2 infection, weight loss and lung pathology Our results show that non-self-reactive virus-neutralizing mAbs elicited during SARS-CoV-2 infection are a promising therapeutic strategy

2.
Elife ; 92020 02 03.
Article in English | MEDLINE | ID: covidwho-774702

ABSTRACT

Bats host virulent zoonotic viruses without experiencing disease. A mechanistic understanding of the impact of bats' virus hosting capacities, including uniquely constitutive immune pathways, on cellular-scale viral dynamics is needed to elucidate zoonotic emergence. We carried out virus infectivity assays on bat cell lines expressing induced and constitutive immune phenotypes, then developed a theoretical model of our in vitro system, which we fit to empirical data. Best fit models recapitulated expected immune phenotypes for representative cell lines, supporting robust antiviral defenses in bat cells that correlated with higher estimates for within-host viral propagation rates. In general, heightened immune responses limit pathogen-induced cellular morbidity, which can facilitate the establishment of rapidly-propagating persistent infections within-host. Rapidly-transmitting viruses that have evolved with bat immune systems will likely cause enhanced virulence following emergence into secondary hosts with immune systems that diverge from those unique to bats.


Subject(s)
Chiroptera/virology , Disease Reservoirs/veterinary , Virus Diseases/veterinary , Viruses/growth & development , Zoonoses/virology , Animals , Cell Line , Chiroptera/immunology , Disease Reservoirs/virology , Host Microbial Interactions , Humans , Immunity, Cellular , Kinetics , Models, Biological , Phenotype , Risk Assessment , Virulence , Virus Diseases/immunology , Virus Diseases/transmission , Virus Diseases/virology , Viruses/immunology , Viruses/pathogenicity , Zoonoses/immunology , Zoonoses/transmission
4.
Emerg Infect Dis ; 26(7): 1592-1595, 2020 07.
Article in English | MEDLINE | ID: covidwho-712728

ABSTRACT

Infection control instructions call for use of alcohol-based hand rub solutions to inactivate severe acute respiratory syndrome coronavirus 2. We determined the virucidal activity of World Health Organization-recommended hand rub formulations, at full strength and multiple dilutions, and of the active ingredients. All disinfectants demonstrated efficient virus inactivation.


Subject(s)
Alcohols/pharmacology , Betacoronavirus/drug effects , Coronavirus Infections/prevention & control , Disinfectants/pharmacology , Hand Disinfection/methods , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Virus Inactivation , Humans , World Health Organization
6.
Nature ; 2020 Jul 29.
Article in English | MEDLINE | ID: covidwho-684778

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the rapidly unfolding coronavirus disease 2019 (COVID-19) pandemic1,2. Clinical manifestations of COVID-19 vary, ranging from asymptomatic infection to respiratory failure. The mechanisms determining such variable outcomes remain unresolved. Here, we investigated SARS-CoV-2 spike glycoprotein (S)-reactive CD4+ T cells in peripheral blood of patients with COVID-19 and SARS-CoV-2-unexposed healthy donors (HD). We detected SARS-CoV-2 S-reactive CD4+ T cells in 83% of patients with COVID-19 but also in 35% of HD. S-reactive CD4+ T cells in HD reacted primarily to C-terminal S epitopes, which show a higher homology to spike glycoproteins of human endemic coronaviruses, compared to N-terminal epitopes. S-reactive T cell lines generated from SARS-CoV-2-naive HD responded similarly to C-terminal S of human endemic coronaviruses 229E and OC43 and SARS-CoV-2, demonstrating the presence of S-cross-reactive T cells, probably generated during past encounters with endemic coronaviruses. The role of pre-existing SARS-CoV-2 cross-reactive T cells for clinical outcomes remains to be determined in larger cohorts. However, the presence of S-cross-reactive T cells in a sizable fraction of the general population may affect the dynamics of the current pandemic, and has important implications for the design and analysis of upcoming COVID-19 vaccine trials.

7.
Nature ; 2020 Jul 22.
Article in English | MEDLINE | ID: covidwho-663955

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been associated with more than 780,000 deaths worldwide (as of 20 August 2020). To develop antiviral interventions quickly, drugs used for the treatment of unrelated diseases are currently being repurposed to treat COVID-19. Chloroquine is an anti-malaria drug that is used for the treatment of COVID-19 as it inhibits the spread of SARS-CoV-2 in the African green monkey kidney-derived cell line Vero1-3. Here we show that engineered expression of TMPRSS2, a cellular protease that activates SARS-CoV-2 for entry into lung cells4, renders SARS-CoV-2 infection of Vero cells insensitive to chloroquine. Moreover, we report that chloroquine does not block infection with SARS-CoV-2 in the TMPRSS2-expressing human lung cell line Calu-3. These results indicate that chloroquine targets a pathway for viral activation that is not active in lung cells and is unlikely to protect against the spread of SARS-CoV-2 in and between patients.

9.
Euro Surveill ; 25(27)2020 07.
Article in English | MEDLINE | ID: covidwho-652787

ABSTRACT

Laboratory preparedness with quality-assured diagnostic assays is essential for controlling the current coronavirus disease (COVID-19) outbreak. We conducted an external quality assessment study with inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) samples to support clinical laboratories with a proficiency testing option for molecular assays. To analyse SARS-CoV-2 testing performance, we used an online questionnaire developed for the European Union project RECOVER to assess molecular testing capacities in clinical diagnostic laboratories.


Subject(s)
Clinical Laboratory Techniques/methods , Clinical Laboratory Techniques/standards , Coronavirus Infections/diagnosis , Coronavirus/isolation & purification , Molecular Diagnostic Techniques/methods , Pandemics , Pneumonia, Viral/diagnosis , Betacoronavirus , Clinical Laboratory Services , Coronavirus Infections/epidemiology , Coronavirus Infections/virology , Disease Outbreaks , Europe , Humans , Pandemics/prevention & control , Pneumonia, Viral/epidemiology , Pneumonia, Viral/virology , Real-Time Polymerase Chain Reaction/standards , Reverse Transcriptase Polymerase Chain Reaction/standards , Sensitivity and Specificity , Surveys and Questionnaires
10.
Emerg Infect Dis ; 26(7):1478-1488, 2020.
Article | WHO COVID | ID: covidwho-655091

ABSTRACT

A new coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has recently emerged to cause a human pandemic Although molecular diagnostic tests were rapidly developed, serologic assays are still lacking, yet urgently needed Validated serologic assays are needed for contact tracing, identifying the viral reservoir, and epidemiologic studies We developed serologic assays for detection of SARS-CoV-2 neutralizing, spike protein-specific, and nucleocapsid-specific antibodies Using serum samples from patients with PCR-confirmed SARS-CoV-2 infections, other coronaviruses, or other respiratory pathogenic infections, we validated and tested various antigens in different in-house and commercial ELISAs We demonstrated that most PCR-confirmed SARS-CoV-2-infected persons seroconverted by 2 weeks after disease onset We found that commercial S1 IgG or IgA ELISAs were of lower specificity, and sensitivity varied between the 2 assays;the IgA ELISA showed higher sensitivity Overall, the validated assays described can be instrumental for detection of SARS-CoV-2-specific antibodies for diagnostic, seroepidemiologic, and vaccine evaluation studies

11.
J Biol Chem ; 2020 Jun 25.
Article in English | MEDLINE | ID: covidwho-615996

ABSTRACT

The recently emerged severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the causative agent of the devastating COVID-19 lung disease pandemic. Here, we tested the inhibitory activities of the antiviral interferons of type I (IFN-alpha) and type III (IFN-lambda) against SARS-CoV-2 and compared them with those against SARS-CoV-1, which emerged in 2003. Using two mammalian epithelial cell lines (human Calu-3 and simian Vero E6), we found that both IFNs dose-dependently inhibit SARS-CoV-2. In contrast, SARS-CoV-1 was restricted only by IFN-alpha in these cell lines. SARS-CoV-2 generally exhibited a broader IFN sensitivity than SARS-CoV-1. Moreover, ruxolitinib, an inhibitor of IFN-triggered Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling, boosted SARS-CoV-2 replication in the IFN-competent Calu-3 cells. We conclude that SARS-CoV-2 is sensitive to exogenously added IFNs. This finding suggests that type I and especially the less adverse effect-prone type III IFN are good candidates for the management of COVID-19.

12.
Nat Biotechnol ; 38(8): 970-979, 2020 08.
Article in English | MEDLINE | ID: covidwho-616612

ABSTRACT

To investigate the immune response and mechanisms associated with severe coronavirus disease 2019 (COVID-19), we performed single-cell RNA sequencing on nasopharyngeal and bronchial samples from 19 clinically well-characterized patients with moderate or critical disease and from five healthy controls. We identified airway epithelial cell types and states vulnerable to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In patients with COVID-19, epithelial cells showed an average three-fold increase in expression of the SARS-CoV-2 entry receptor ACE2, which correlated with interferon signals by immune cells. Compared to moderate cases, critical cases exhibited stronger interactions between epithelial and immune cells, as indicated by ligand-receptor expression profiles, and activated immune cells, including inflammatory macrophages expressing CCL2, CCL3, CCL20, CXCL1, CXCL3, CXCL10, IL8, IL1B and TNF. The transcriptional differences in critical cases compared to moderate cases likely contribute to clinical observations of heightened inflammatory tissue damage, lung injury and respiratory failure. Our data suggest that pharmacologic inhibition of the CCR1 and/or CCR5 pathways might suppress immune hyperactivation in critical COVID-19.


Subject(s)
Coronavirus Infections/pathology , Coronavirus Infections/physiopathology , Pneumonia, Viral/pathology , Pneumonia, Viral/physiopathology , Respiratory System/pathology , Single-Cell Analysis , Transcriptome , Adult , Aged , Bronchoalveolar Lavage Fluid/virology , Cell Communication , Cell Differentiation , Coronavirus Infections/virology , Epithelial Cells/pathology , Epithelial Cells/virology , Female , Humans , Immune System/pathology , Inflammation/immunology , Inflammation/pathology , Longitudinal Studies , Male , Middle Aged , Nasopharynx/virology , Pandemics , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/virology , Respiratory System/immunology , Respiratory System/virology , Severity of Illness Index
13.
Euro Surveill ; 25(24)2020 06.
Article in English | MEDLINE | ID: covidwho-605372

ABSTRACT

Containment strategies and clinical management of coronavirus disease (COVID-19) patients during the current pandemic depend on reliable diagnostic PCR assays for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we compare 11 different RT-PCR test systems used in seven diagnostic laboratories in Germany in March 2020. While most assays performed well, we identified detection problems in a commonly used assay that may have resulted in false-negative test results during the first weeks of the pandemic.


Subject(s)
Betacoronavirus/genetics , Clinical Laboratory Techniques/methods , Coronavirus Infections/diagnosis , Diagnostic Equipment , Pneumonia, Viral/diagnosis , Clinical Laboratory Techniques/instrumentation , Feces/virology , Germany , Humans , Laboratories , Multiplex Polymerase Chain Reaction/instrumentation , Multiplex Polymerase Chain Reaction/methods , Pandemics , Real-Time Polymerase Chain Reaction/instrumentation , Real-Time Polymerase Chain Reaction/methods , Reverse Transcriptase Polymerase Chain Reaction/instrumentation , Reverse Transcriptase Polymerase Chain Reaction/methods , Sensitivity and Specificity
14.
Infection ; 48(4): 619-626, 2020 Aug.
Article in English | MEDLINE | ID: covidwho-597401

ABSTRACT

PURPOSE: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide causing a global health emergency. Pa-COVID-19 aims to provide comprehensive data on clinical course, pathophysiology, immunology and outcome of COVID-19, to identify prognostic biomarkers, clinical scores, and therapeutic targets for improved clinical management and preventive interventions. METHODS: Pa-COVID-19 is a prospective observational cohort study of patients with confirmed SARS-CoV-2 infection treated at Charité - Universitätsmedizin Berlin. We collect data on epidemiology, demography, medical history, symptoms, clinical course, and pathogen testing and treatment. Systematic, serial blood sampling will allow deep molecular and immunological phenotyping, transcriptomic profiling, and comprehensive biobanking. Longitudinal data and sample collection during hospitalization will be supplemented by long-term follow-up. RESULTS: Outcome measures include the WHO clinical ordinal scale on day 15 and clinical, functional, and health-related quality-of-life assessments at discharge and during follow-up. We developed a scalable dataset to (i) suit national standards of care, (ii) facilitate comprehensive data collection in medical care facilities with varying resources, and (iii) allow for rapid implementation of interventional trials based on the standardized study design and data collection. We propose this scalable protocol as blueprint for harmonized data collection and deep phenotyping in COVID-19 in Germany. CONCLUSION: We established a basic platform for harmonized, scalable data collection, pathophysiological analysis, and deep phenotyping of COVID-19, which enables rapid generation of evidence for improved medical care and identification of candidate therapeutic and preventive strategies. The electronic database accredited for interventional trials allows fast trial implementation for candidate therapeutic agents. TRIAL REGISTRATION: Registered at the German registry for clinical studies (DRKS00021688).


Subject(s)
Coronavirus Infections/physiopathology , Pneumonia, Viral/physiopathology , Registries , Berlin/epidemiology , Betacoronavirus , Biological Specimen Banks , Coronavirus Infections/epidemiology , Disease Management , Humans , Observational Studies as Topic , Pandemics , Phenotype , Pneumonia, Viral/epidemiology , Prospective Studies , Risk Assessment , Risk Factors , Time Factors , Treatment Outcome , World Health Organization
15.
Cell Syst ; 11(1): 11-24.e4, 2020 07 22.
Article in English | MEDLINE | ID: covidwho-459007

ABSTRACT

The COVID-19 pandemic is an unprecedented global challenge, and point-of-care diagnostic classifiers are urgently required. Here, we present a platform for ultra-high-throughput serum and plasma proteomics that builds on ISO13485 standardization to facilitate simple implementation in regulated clinical laboratories. Our low-cost workflow handles up to 180 samples per day, enables high precision quantification, and reduces batch effects for large-scale and longitudinal studies. We use our platform on samples collected from a cohort of early hospitalized cases of the SARS-CoV-2 pandemic and identify 27 potential biomarkers that are differentially expressed depending on the WHO severity grade of COVID-19. They include complement factors, the coagulation system, inflammation modulators, and pro-inflammatory factors upstream and downstream of interleukin 6. All protocols and software for implementing our approach are freely available. In total, this work supports the development of routine proteomic assays to aid clinical decision making and generate hypotheses about potential COVID-19 therapeutic targets.


Subject(s)
Blood Proteins/metabolism , Coronavirus Infections/blood , Pneumonia, Viral/blood , Proteomics/methods , Adult , Aged , Aged, 80 and over , Betacoronavirus/isolation & purification , Biomarkers/blood , Blood Proteins/analysis , Coronavirus Infections/classification , Coronavirus Infections/pathology , Coronavirus Infections/virology , Female , Humans , Male , Middle Aged , Pandemics/classification , Pneumonia, Viral/classification , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , Young Adult
17.
Emerg Microbes Infect ; 9(1): 155-168, 2020.
Article in English | MEDLINE | ID: covidwho-326251

ABSTRACT

Middle East respiratory syndrome (MERS) coronavirus (MERS-CoV) causes a severe respiratory disease in humans. The MERS-CoV spike (S) glycoprotein mediates viral entry into target cells. For this, MERS-CoV S engages the host cell protein dipeptidyl peptidase 4 (DPP4, CD26) and the interface between MERS-CoV S and DPP4 has been resolved on the atomic level. Here, we asked whether naturally-occurring polymorphisms in DPP4, that alter amino acid residues required for MERS-CoV S binding, influence cellular entry of MERS-CoV. By screening of public databases, we identified fourteen such polymorphisms. Introduction of the respective mutations into DPP4 revealed that all except one (Δ346-348) were compatible with robust DPP4 expression. Four polymorphisms (K267E, K267N, A291P and Δ346-348) strongly reduced binding of MERS-CoV S to DPP4 and S protein-driven host cell entry, as determined using soluble S protein and S protein bearing rhabdoviral vectors, respectively. Two polymorphisms (K267E and A291P) were analyzed in the context of authentic MERS-CoV and were found to attenuate viral replication. Collectively, we identified naturally-occurring polymorphisms in DPP4 that negatively impact cellular entry of MERS-CoV and might thus modulate MERS development in infected patients.


Subject(s)
Coronavirus Infections/genetics , Dipeptidyl Peptidase 4/genetics , Middle East Respiratory Syndrome Coronavirus/physiology , Virus Internalization , Coronavirus Infections/immunology , Coronavirus Infections/virology , Dipeptidyl Peptidase 4/immunology , Host-Pathogen Interactions , Humans , Middle East Respiratory Syndrome Coronavirus/genetics , Polymorphism, Genetic
18.
Lancet Infect Dis ; 20(8): 920-928, 2020 08.
Article in English | MEDLINE | ID: covidwho-276988

ABSTRACT

BACKGROUND: In December, 2019, the newly identified severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, China, causing COVID-19, a respiratory disease presenting with fever, cough, and often pneumonia. WHO has set the strategic objective to interrupt spread of SARS-CoV-2 worldwide. An outbreak in Bavaria, Germany, starting at the end of January, 2020, provided the opportunity to study transmission events, incubation period, and secondary attack rates. METHODS: A case was defined as a person with SARS-CoV-2 infection confirmed by RT-PCR. Case interviews were done to describe timing of onset and nature of symptoms and to identify and classify contacts as high risk (had cumulative face-to-face contact with a confirmed case for ≥15 min, direct contact with secretions or body fluids of a patient with confirmed COVID-19, or, in the case of health-care workers, had worked within 2 m of a patient with confirmed COVID-19 without personal protective equipment) or low risk (all other contacts). High-risk contacts were ordered to stay at home in quarantine for 14 days and were actively followed up and monitored for symptoms, and low-risk contacts were tested upon self-reporting of symptoms. We defined fever and cough as specific symptoms, and defined a prodromal phase as the presence of non-specific symptoms for at least 1 day before the onset of specific symptoms. Whole genome sequencing was used to confirm epidemiological links and clarify transmission events where contact histories were ambiguous; integration with epidemiological data enabled precise reconstruction of exposure events and incubation periods. Secondary attack rates were calculated as the number of cases divided by the number of contacts, using Fisher's exact test for the 95% CIs. FINDINGS: Patient 0 was a Chinese resident who visited Germany for professional reasons. 16 subsequent cases, often with mild and non-specific symptoms, emerged in four transmission generations. Signature mutations in the viral genome occurred upon foundation of generation 2, as well as in one case pertaining to generation 4. The median incubation period was 4·0 days (IQR 2·3-4·3) and the median serial interval was 4·0 days (3·0-5·0). Transmission events were likely to have occurred presymptomatically for one case (possibly five more), at the day of symptom onset for four cases (possibly five more), and the remainder after the day of symptom onset or unknown. One or two cases resulted from contact with a case during the prodromal phase. Secondary attack rates were 75·0% (95% CI 19·0-99·0; three of four people) among members of a household cluster in common isolation, 10·0% (1·2-32·0; two of 20) among household contacts only together until isolation of the patient, and 5·1% (2·6-8·9; 11 of 217) among non-household, high-risk contacts. INTERPRETATION: Although patients in our study presented with predominately mild, non-specific symptoms, infectiousness before or on the day of symptom onset was substantial. Additionally, the incubation period was often very short and false-negative tests occurred. These results suggest that although the outbreak was controlled, successful long-term and global containment of COVID-19 could be difficult to achieve. FUNDING: All authors are employed and all expenses covered by governmental, federal state, or other publicly funded institutions.


Subject(s)
Betacoronavirus/isolation & purification , Communicable Diseases, Imported/transmission , Coronavirus Infections/transmission , Disease Outbreaks , Disease Transmission, Infectious , Pneumonia, Viral/transmission , Travel-Related Illness , Adolescent , Adult , Betacoronavirus/classification , Betacoronavirus/genetics , Child , Child, Preschool , China , Communicable Diseases, Imported/epidemiology , Communicable Diseases, Imported/pathology , Communicable Diseases, Imported/virology , Coronavirus Infections/epidemiology , Germany/epidemiology , Humans , Interviews as Topic , Middle Aged , Mutation , Pandemics , Pneumonia, Viral/epidemiology , RNA, Viral/genetics , Reverse Transcriptase Polymerase Chain Reaction , Risk Assessment , Travel , Young Adult
19.
Transfusion ; 60(6): 1119-1122, 2020 06.
Article in English | MEDLINE | ID: covidwho-176102

ABSTRACT

Oral swabs, sputum, and blood samples from 18 asymptomatic and symptomatic patients with SARS-CoV-2 infection were examined using RT-PCR testing in order to assess the risk of transfusion-related transmission. In asymptomatic patients as well as patients with flu-like symptoms and fever, no SARS-CoV-2 RNA could be detected in the blood or serum despite a clearly positive result in all throat swabs. As patients with symptoms of infectious disease will not be admitted to blood donation, the risk for transfusion transmission of SARS-CoV-2 seems to be negligible.


Subject(s)
Asymptomatic Infections , Betacoronavirus/isolation & purification , Blood Donors , Blood Safety , Coronavirus Infections/transmission , Donor Selection , Pneumonia, Viral/transmission , Transfusion Reaction/prevention & control , Adolescent , Adult , Aged , Coronavirus Infections/blood , Coronavirus Infections/diagnosis , Female , Germany , Humans , Male , Middle Aged , Pandemics , Pneumonia, Viral/blood , Pneumonia, Viral/diagnosis , Transfusion Reaction/virology , Young Adult
20.
Science ; 368(6489): 409-412, 2020 04 24.
Article in English | MEDLINE | ID: covidwho-164984

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is a global health emergency. An attractive drug target among coronaviruses is the main protease (Mpro, also called 3CLpro) because of its essential role in processing the polyproteins that are translated from the viral RNA. We report the x-ray structures of the unliganded SARS-CoV-2 Mpro and its complex with an α-ketoamide inhibitor. This was derived from a previously designed inhibitor but with the P3-P2 amide bond incorporated into a pyridone ring to enhance the half-life of the compound in plasma. On the basis of the unliganded structure, we developed the lead compound into a potent inhibitor of the SARS-CoV-2 Mpro The pharmacokinetic characterization of the optimized inhibitor reveals a pronounced lung tropism and suitability for administration by the inhalative route.


Subject(s)
Amides/chemistry , Amides/pharmacology , Betacoronavirus/drug effects , Betacoronavirus/enzymology , Cysteine Endopeptidases/chemistry , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Viral Nonstructural Proteins/chemistry , Amides/metabolism , Animals , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Antiviral Agents/pharmacokinetics , Antiviral Agents/pharmacology , Binding Sites , Cell Line, Tumor , Crystallography, X-Ray , Cysteine Endopeptidases/metabolism , Drug Design , Half-Life , Humans , Lung/metabolism , Mice , Models, Molecular , Protease Inhibitors/metabolism , Protease Inhibitors/pharmacokinetics , Protein Domains , Protein Multimerization , Pyridones/chemistry , Viral Nonstructural Proteins/metabolism , Virus Replication/drug effects
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