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1.
Cell Rep ; 37(4): 109882, 2021 10 26.
Article in English | MEDLINE | ID: covidwho-1525720

ABSTRACT

Remdesivir (RDV), a nucleotide analog with broad-spectrum features, has exhibited effectiveness in COVID-19 treatment. However, the precise working mechanism of RDV when targeting the viral RNA-dependent RNA polymerase (RdRP) has not been fully elucidated. Here, we solve a 3.0-Å structure of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RdRP elongation complex (EC) and assess RDV intervention in polymerase elongation phase. Although RDV could induce an "i+3" delayed termination in meta-stable complexes, only pausing and subsequent elongation are observed in the EC. A comparative investigation using an enterovirus RdRP further confirms similar delayed intervention and demonstrates that steric hindrance of the RDV-characteristic 1'-cyano at the -4 position is responsible for the "i+3" intervention, although two representative Flaviviridae RdRPs do not exhibit similar behavior. A comparison of representative viral RdRP catalytic complex structures indicates that the product RNA backbone encounters highly conserved structural elements, highlighting the broad-spectrum intervention potential of 1'-modified nucleotide analogs in anti-RNA virus drug development.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/pharmacology , RNA-Dependent RNA Polymerase/drug effects , SARS-CoV-2/drug effects , Viral Proteins/drug effects , Adenosine Monophosphate/pharmacology , Alanine/pharmacology , COVID-19/drug therapy , Cryoelectron Microscopy , Humans , RNA, Viral/chemistry , RNA, Viral/drug effects , RNA-Dependent RNA Polymerase/chemistry , SARS-CoV-2/chemistry , Viral Proteins/chemistry , Virus Replication/drug effects
2.
Nucleic Acids Res ; 48(3): 1392-1405, 2020 02 20.
Article in English | MEDLINE | ID: covidwho-1332861

ABSTRACT

The enterovirus 71 (EV71) 3Dpol is an RNA-dependent RNA polymerase (RdRP) that plays the central role in the viral genome replication, and is an important target in antiviral studies. Here, we report a crystal structure of EV71 3Dpol elongation complex (EC) at 1.8 Å resolution. The structure reveals that the 5'-end guanosine of the downstream RNA template interacts with a fingers domain pocket, with the base sandwiched by H44 and R277 side chains through hydrophobic stacking interactions, and these interactions are still maintained after one in-crystal translocation event induced by nucleotide incorporation, implying that the pocket could regulate the functional properties of the polymerase by interacting with RNA. When mutated, residue R277 showed an impact on virus proliferation in virological studies with residue H44 having a synergistic effect. In vitro biochemical data further suggest that mutations at these two sites affect RNA binding, EC stability, but not polymerase catalytic rate (kcat) and apparent NTP affinity (KM,NTP). We propose that, although rarely captured by crystallography, similar surface pocket interaction with nucleobase may commonly exist in nucleic acid motor enzymes to facilitate their processivity. Potential applications in antiviral drug and vaccine development are also discussed.


Subject(s)
Enterovirus A, Human/ultrastructure , Multiprotein Complexes/ultrastructure , Protein Conformation , RNA-Dependent RNA Polymerase/ultrastructure , Antiviral Agents/chemistry , Binding Sites , Crystallography, X-Ray , Enterovirus A, Human/chemistry , Enterovirus A, Human/genetics , Genome, Viral , Humans , Models, Molecular , Multiprotein Complexes/chemistry , Nucleotides/chemistry , RNA, Viral/chemistry , RNA, Viral/ultrastructure , RNA-Dependent RNA Polymerase/chemistry , Virus Replication/genetics
3.
Int J Environ Res Public Health ; 18(6)2021 03 10.
Article in English | MEDLINE | ID: covidwho-1125260

ABSTRACT

Mobility restrictions have been a heated topic during the global pandemic of coronavirus disease 2019 (COVID-19). However, multiple recent findings have verified its importance in blocking virus spread. Evidence on the association between mobility, cases imported from abroad and local medical resource supplies is limited. To reveal the association, this study quantified the importance of inter- and intra-country mobility in containing virus spread and avoiding hospitalizations during early stages of COVID-19 outbreaks in India, Japan, and China. We calculated the time-varying reproductive number (Rt) and duration from illness onset to diagnosis confirmation (Doc), to represent conditions of virus spread and hospital bed shortages, respectively. Results showed that inter-country mobility fluctuation could explain 80%, 35%, and 12% of the variance in imported cases and could prevent 20 million, 5 million, and 40 million imported cases in India, Japan and China, respectively. The critical time for screening and monitoring of imported cases is 2 weeks at minimum and 4 weeks at maximum, according to the time when the Pearson's Rs between Rt and imported cases reaches a peak (>0.8). We also found that if local transmission is initiated, a 1% increase in intra-country mobility would result in 1430 (±501), 109 (±181), and 10 (±1) additional bed shortages, as estimated using the Doc in India, Japan, and China, respectively. Our findings provide vital reference for governments to tailor their pre-vaccination policies regarding mobility, especially during future epidemic waves of COVID-19 or similar severe epidemic outbreaks.


Subject(s)
COVID-19 , China/epidemiology , Disease Outbreaks , Humans , India/epidemiology , Japan/epidemiology , SARS-CoV-2
4.
Environ Health Perspect ; 128(11): 115001, 2020 11.
Article in English | MEDLINE | ID: covidwho-1054874

ABSTRACT

BACKGROUND: Modeling suggests that climate change mitigation actions can have substantial human health benefits that accrue quickly and locally. Documenting the benefits can help drive more ambitious and health-protective climate change mitigation actions; however, documenting the adverse health effects can help to avoid them. Estimating the health effects of mitigation (HEM) actions can help policy makers prioritize investments based not only on mitigation potential but also on expected health benefits. To date, however, the wide range of incompatible approaches taken to developing and reporting HEM estimates has limited their comparability and usefulness to policymakers. OBJECTIVE: The objective of this effort was to generate guidance for modeling studies on scoping, estimating, and reporting population health effects from climate change mitigation actions. METHODS: An expert panel of HEM researchers was recruited to participate in developing guidance for conducting HEM studies. The primary literature and a synthesis of HEM studies were provided to the panel. Panel members then participated in a modified Delphi exercise to identify areas of consensus regarding HEM estimation. Finally, the panel met to review and discuss consensus findings, resolve remaining differences, and generate guidance regarding conducting HEM studies. RESULTS: The panel generated a checklist of recommendations regarding stakeholder engagement: HEM modeling, including model structure, scope and scale, demographics, time horizons, counterfactuals, health response functions, and metrics; parameterization and reporting; approaches to uncertainty and sensitivity analysis; accounting for policy uptake; and discounting. DISCUSSION: This checklist provides guidance for conducting and reporting HEM estimates to make them more comparable and useful for policymakers. Harmonization of HEM estimates has the potential to lead to advances in and improved synthesis of policy-relevant research that can inform evidence-based decision making and practice. https://doi.org/10.1289/EHP6745.


Subject(s)
Air Pollution , COVID-19 , Coronavirus , Severe Acute Respiratory Syndrome , Climate Change , Disease Outbreaks , Epidemiologic Studies , Humans , SARS-CoV-2
6.
Preprint | SciFinder | ID: ppcovidwho-4407

ABSTRACT

A review. Novel coronavirus (2019-nCoV) detected at the end of 2019 is an RNA virus that belongs to Coronaviridae, which spreads fast and causes serious consequences to human health. infection with 2019-nCoV leads to severe pneumonia in humans, however, there is no cure for this disease. Early diagnosis of 2019-nCoV is one critical step towards preventing the outbreak of 2019-nCoV and helping cure patients. As a result, an early laboratory diagnostic method with high specificity and sensitivity is indeed needed now. in this review, we summarize the methods for diagnosis that have been used in diagnosis of 2019-nCoV or other disease, which may contribute to constructing better methods for early diagnosis of 2019-nCoV.

8.
Nat Commun ; 11(1): 5172, 2020 10 14.
Article in English | MEDLINE | ID: covidwho-963670

ABSTRACT

The COVID-19 pandemic is impacting human activities, and in turn energy use and carbon dioxide (CO2) emissions. Here we present daily estimates of country-level CO2 emissions for different sectors based on near-real-time activity data. The key result is an abrupt 8.8% decrease in global CO2 emissions (-1551 Mt CO2) in the first half of 2020 compared to the same period in 2019. The magnitude of this decrease is larger than during previous economic downturns or World War II. The timing of emissions decreases corresponds to lockdown measures in each country. By July 1st, the pandemic's effects on global emissions diminished as lockdown restrictions relaxed and some economic activities restarted, especially in China and several European countries, but substantial differences persist between countries, with continuing emission declines in the U.S. where coronavirus cases are still increasing substantially.


Subject(s)
Air Pollutants/analysis , Carbon Dioxide/analysis , Coronavirus Infections/epidemiology , Pneumonia, Viral/epidemiology , Air Pollutants/economics , Betacoronavirus , COVID-19 , Carbon Dioxide/economics , Coronavirus Infections/economics , Coronavirus Infections/prevention & control , Environmental Monitoring , Fossil Fuels/analysis , Fossil Fuels/economics , Humans , Industry/economics , Nitrogen Dioxide/analysis , Nitrogen Dioxide/economics , Pandemics/economics , Pandemics/prevention & control , Pneumonia, Viral/economics , Pneumonia, Viral/prevention & control , SARS-CoV-2
9.
Proc Natl Acad Sci U S A ; 117(42): 26151-26157, 2020 10 20.
Article in English | MEDLINE | ID: covidwho-807983

ABSTRACT

Emerging evidence suggests a resurgence of COVID-19 in the coming years. It is thus critical to optimize emergency response planning from a broad, integrated perspective. We developed a mathematical model incorporating climate-driven variation in community transmissions and movement-modulated spatial diffusions of COVID-19 into various intervention scenarios. We find that an intensive 8-wk intervention targeting the reduction of local transmissibility and international travel is efficient and effective. Practically, we suggest a tiered implementation of this strategy where interventions are first implemented at locations in what we call the Global Intervention Hub, followed by timely interventions in secondary high-risk locations. We argue that thinking globally, categorizing locations in a hub-and-spoke intervention network, and acting locally, applying interventions at high-risk areas, is a functional strategy to avert the tremendous burden that would otherwise be placed on public health and society.


Subject(s)
Communicable Disease Control/methods , Communicable Diseases, Emerging/prevention & control , Coronavirus Infections/prevention & control , Disease Transmission, Infectious/prevention & control , Global Health/trends , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Betacoronavirus , COVID-19 , Climate , Communicable Diseases, Emerging/epidemiology , Communicable Diseases, Emerging/transmission , Coronavirus Infections/epidemiology , Coronavirus Infections/transmission , Forecasting , Humans , International Cooperation , Models, Theoretical , Pneumonia, Viral/epidemiology , Pneumonia, Viral/transmission , SARS-CoV-2 , Travel
10.
Nat Hum Behav ; 4(6): 577-587, 2020 06.
Article in English | MEDLINE | ID: covidwho-563084

ABSTRACT

Countries have sought to stop the spread of coronavirus disease 2019 (COVID-19) by severely restricting travel and in-person commercial activities. Here, we analyse the supply-chain effects of a set of idealized lockdown scenarios, using the latest global trade modelling framework. We find that supply-chain losses that are related to initial COVID-19 lockdowns are largely dependent on the number of countries imposing restrictions and that losses are more sensitive to the duration of a lockdown than its strictness. However, a longer containment that can eradicate the disease imposes a smaller loss than shorter ones. Earlier, stricter and shorter lockdowns can minimize overall losses. A 'go-slow' approach to lifting restrictions may reduce overall damages if it avoids the need for further lockdowns. Regardless of the strategy, the complexity of global supply chains will magnify losses beyond the direct effects of COVID-19. Thus, pandemic control is a public good that requires collective efforts and support to lower-capacity countries.


Subject(s)
Communicable Disease Control , Coronavirus Infections , Health Policy , Industry , Models, Econometric , Pandemics , Pneumonia, Viral , COVID-19 , Communicable Disease Control/economics , Coronavirus Infections/economics , Coronavirus Infections/prevention & control , Health Policy/economics , Humans , Industry/economics , Pandemics/economics , Pandemics/prevention & control , Pneumonia, Viral/economics , Pneumonia, Viral/prevention & control
11.
Cell ; 182(2): 417-428.e13, 2020 07 23.
Article in English | MEDLINE | ID: covidwho-342735

ABSTRACT

Nucleotide analog inhibitors, including broad-spectrum remdesivir and favipiravir, have shown promise in in vitro assays and some clinical studies for COVID-19 treatment, this despite an incomplete mechanistic understanding of the viral RNA-dependent RNA polymerase nsp12 drug interactions. Here, we examine the molecular basis of SARS-CoV-2 RNA replication by determining the cryo-EM structures of the stalled pre- and post- translocated polymerase complexes. Compared with the apo complex, the structures show notable structural rearrangements happening to nsp12 and its co-factors nsp7 and nsp8 to accommodate the nucleic acid, whereas there are highly conserved residues in nsp12, positioning the template and primer for an in-line attack on the incoming nucleotide. Furthermore, we investigate the inhibition mechanism of the triphosphate metabolite of remdesivir through structural and kinetic analyses. A transition model from the nsp7-nsp8 hexadecameric primase complex to the nsp12-nsp7-nsp8 polymerase complex is also proposed to provide clues for the understanding of the coronavirus transcription and replication machinery.


Subject(s)
Betacoronavirus/chemistry , Betacoronavirus/enzymology , RNA-Dependent RNA Polymerase/chemistry , Viral Nonstructural Proteins/chemistry , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/chemistry , Adenosine Monophosphate/metabolism , Adenosine Monophosphate/pharmacology , Alanine/analogs & derivatives , Alanine/chemistry , Alanine/metabolism , Alanine/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Antiviral Agents/pharmacology , Catalytic Domain , Coronavirus RNA-Dependent RNA Polymerase , Cryoelectron Microscopy , Models, Chemical , Models, Molecular , RNA, Viral/metabolism , SARS-CoV-2 , Transcription, Genetic , Virus Replication
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