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1.
Preprint in English | EuropePMC | ID: ppcovidwho-292298

ABSTRACT

Essential oils and aromatic extracts (oleoresins, absolutes, concretes, resinoids) are often used as food flavorings and constituents of fragrance compositions. The flavor and fragrance industry observes significant growth in sales of some natural materials during the COVID-19 outbreak. Some companies worldwide are making false claims regarding their essential oils or blends to be effective (or indirectly points towards this conclusion) against coronaviruses even though the available data on the activity of plant materials against highly pathogenic human coronaviruses is very scarce. Our exploratory study aimed to develop pioneering knowledge and provide the first experimental results on the inhibitory properties of hundreds of flavor & fragrance materials against SARS-CoV-2 main- and papain-like proteases, and antiviral potential of the most active protease inhibitors. As essential oils are volatile products, they could provide an interesting subsidiary inhalation therapeutic strategy in the long term.

2.
Preprint in English | EuropePMC | ID: ppcovidwho-292297

ABSTRACT

Essential oils and aromatic extracts (oleoresins, absolutes, concretes, resinoids) are often used as food flavorings and constituents of fragrance compositions. The flavor and fragrance industry observes significant growth in sales of some natural materials during the COVID-19 outbreak. Some companies worldwide are making false claims regarding their essential oils or blends to be effective (or indirectly points towards this conclusion) against coronaviruses even though the available data on the activity of plant materials against highly pathogenic human coronaviruses is very scarce. Our exploratory study aimed to develop pioneering knowledge, and provide the first experimental results on the inhibitory properties of hundreds of flavor & fragrance materials against SARS-CoV-2 main- and papain-like proteases. As essential oils are volatile products, they could provide an interesting subsidiary inhalation therapeutic strategy in the long term.

3.
Nat Neurosci ; 24(11): 1522-1533, 2021 11.
Article in English | MEDLINE | ID: covidwho-1500484

ABSTRACT

Coronavirus disease 2019 (COVID-19) can damage cerebral small vessels and cause neurological symptoms. Here we describe structural changes in cerebral small vessels of patients with COVID-19 and elucidate potential mechanisms underlying the vascular pathology. In brains of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected individuals and animal models, we found an increased number of empty basement membrane tubes, so-called string vessels representing remnants of lost capillaries. We obtained evidence that brain endothelial cells are infected and that the main protease of SARS-CoV-2 (Mpro) cleaves NEMO, the essential modulator of nuclear factor-κB. By ablating NEMO, Mpro induces the death of human brain endothelial cells and the occurrence of string vessels in mice. Deletion of receptor-interacting protein kinase (RIPK) 3, a mediator of regulated cell death, blocks the vessel rarefaction and disruption of the blood-brain barrier due to NEMO ablation. Importantly, a pharmacological inhibitor of RIPK signaling prevented the Mpro-induced microvascular pathology. Our data suggest RIPK as a potential therapeutic target to treat the neuropathology of COVID-19.


Subject(s)
Blood-Brain Barrier/metabolism , Brain/metabolism , Coronavirus 3C Proteases/metabolism , Intracellular Signaling Peptides and Proteins/metabolism , Microvessels/metabolism , SARS-CoV-2/metabolism , Animals , Blood-Brain Barrier/pathology , Brain/pathology , Chlorocebus aethiops , Coronavirus 3C Proteases/genetics , Cricetinae , Female , Humans , Intracellular Signaling Peptides and Proteins/genetics , Male , Mesocricetus , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Microvessels/pathology , SARS-CoV-2/genetics , Vero Cells
4.
Nat Neurosci ; 24(11): 1522-1533, 2021 11.
Article in English | MEDLINE | ID: covidwho-1483143

ABSTRACT

Coronavirus disease 2019 (COVID-19) can damage cerebral small vessels and cause neurological symptoms. Here we describe structural changes in cerebral small vessels of patients with COVID-19 and elucidate potential mechanisms underlying the vascular pathology. In brains of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected individuals and animal models, we found an increased number of empty basement membrane tubes, so-called string vessels representing remnants of lost capillaries. We obtained evidence that brain endothelial cells are infected and that the main protease of SARS-CoV-2 (Mpro) cleaves NEMO, the essential modulator of nuclear factor-κB. By ablating NEMO, Mpro induces the death of human brain endothelial cells and the occurrence of string vessels in mice. Deletion of receptor-interacting protein kinase (RIPK) 3, a mediator of regulated cell death, blocks the vessel rarefaction and disruption of the blood-brain barrier due to NEMO ablation. Importantly, a pharmacological inhibitor of RIPK signaling prevented the Mpro-induced microvascular pathology. Our data suggest RIPK as a potential therapeutic target to treat the neuropathology of COVID-19.


Subject(s)
Blood-Brain Barrier/metabolism , Brain/metabolism , Coronavirus 3C Proteases/metabolism , Intracellular Signaling Peptides and Proteins/metabolism , Microvessels/metabolism , SARS-CoV-2/metabolism , Animals , Blood-Brain Barrier/pathology , Brain/pathology , Chlorocebus aethiops , Coronavirus 3C Proteases/genetics , Cricetinae , Female , Humans , Intracellular Signaling Peptides and Proteins/genetics , Male , Mesocricetus , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Microvessels/pathology , SARS-CoV-2/genetics , Vero Cells
5.
Sustainability ; 13(8):4141, 2021.
Article in English | ProQuest Central | ID: covidwho-1362546

ABSTRACT

Alleviating human sufferings during and in the aftermath of disasters is one of the most important goals in humanitarian relief logistics. The lack of relief commodities, especially life-saving items, is a life-threatening loss to victims and must be considered when making emergency supply allocation and transportation decisions, even in the pre-disaster prepositioning phase. This paper proposes a scenario-based stochastic program that integrates the decisions of prepositioning facility locations, quantities of stocked emergency supplies, and service allocations in each scenario in the same modeling framework. The estimation of victims’ losses for waiting for emergency supplies is measured in the typical deprivation cost function and treated as one of the main bases of decision making, besides traditional transportation costs, in determining the service allocation strategies in each scenario. Specifically, a case study with data from the hurricane threat in the Gulf Coast area of the US was conducted to demonstrate the application of this model and the significance of considering victims’ welfare loss in humanitarian relief logistics. Some interesting managerial insights were also drawn from a series of numerical experiments and sensitivity analyses.

6.
Research of Environmental Sciences ; 33(7):1632-1639, 2020.
Article in Chinese | GIM | ID: covidwho-1196352

ABSTRACT

Chlorine disinfectants were widely used during the coronavirus disease(COVID-19). Water quality and human health might be affected by chlorine residues. Residual chlorine and its guideline value was not set in the quality standards of drinking water sources in China. The lack of result evaluation and standards of field rapid analysis methods were also problems to be solved.In order to provide a reference for monitoring and evaluation of residual chlorine in water in public health events, the domestic and international guideline values, laboratory analysis standards and field rapid analysis methods for residual chlorine in drinking water were summarized. The results showed that:(1) The guideline values of residual chlorine in the distribution systems(0.1-2.0 mg/L) and at the point of delivery(0.1-1.8 mg/L), and the maximum concentration of residual chlorine in drinking water(4-5 mg/L) were set by other countries, regions and WHO.(2) Colorimetric and titrimetric methods were considered as standards or recommended analytical methods for laboratories because of their rapid response,stability, high accuracy and high precision. High performance liquid chromatography(HPLC) could also be applied for trace analysis of residual chlorine due to its low detection limit and high sensitivity.(3) Most field rapid analysis and on-line monitoring methods were colorimetric and electrochemical methods, but there was no uniform standard method. The research showed that the maximum concentration of residual chlorine in drinking water in foreign countries, regions or organizations was 5 mg/L. The recommended minimum concentrations for residual chlorine to point of delivery were 0.5 mg/L in high-risk circumstances.It was suggested to carry out the standardization research on the field monitoring methods of water.

8.
Chinese Journal of Biologicals ; 33(12):1409-1413, 2020.
Article in Chinese | GIM | ID: covidwho-1073828

ABSTRACT

Objective: To systematically analyze the 670 convalescent plasma (CP) samples from patients with coronavirus disease 2019 (COVID-19).

9.
J Diabetes ; 13(3): 243-252, 2021 Mar.
Article in English | MEDLINE | ID: covidwho-933955

ABSTRACT

BACKGROUND: Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is currently posing significant threats to public health worldwide. It is notable that a substantial proportion of patients with sever COVID-19 have coexisting diabetic conditions, indicating the progression and outcome of COVID-19 may relate to diabetes. However, it is still unclear whether diabetic treatment principles can be used for the treatment of COVID-19. METHODS: We conducted a computational approach to screen all commonly used clinical oral hypoglycemic drugs to identify the potential inhibitors for the main protease (Mpro ) of SARS-CoV-2, which is one of the key drug targets for anti-COVID-19 drug discovery. RESULTS: Six antidiabetic drugs with docking scores higher than 8.0 (cutoff value), including repaglinide, canagliflozin, glipizide, gliquidone, glimepiride, and linagliptin, were predicted as the promising inhibitors of Mpro . Interestingly, repaglinide, one of the six antidiabetic drugs with the highest docking score for Mpro , was similar to a previously predicted active molecule nelfinavir, which is a potential anti-HIV and anti-COVID-19 drug. Moreover, we found repaglinide shared similar docking pose and pharmacophores with a reported ligand (N3 inhibitor) and nelfinavir, demonstrating that repaglinide would interact with Mpro in a similar way. CONCLUSION: These results indicated that these six antidiabetic drugs may have an extra effect on the treatment of COVID-19, although further studies are necessary to confirm these findings.


Subject(s)
COVID-19/drug therapy , Hypoglycemic Agents/pharmacology , Viral Matrix Proteins/antagonists & inhibitors , A549 Cells , Antiviral Agents/pharmacology , Binding Sites , Drug Discovery , Humans , Models, Molecular , Molecular Docking Simulation , Molecular Dynamics Simulation , Nelfinavir/pharmacology , Protease Inhibitors/pharmacology
10.
Nat Chem Biol ; 17(2): 222-228, 2021 02.
Article in English | MEDLINE | ID: covidwho-899948

ABSTRACT

In December 2019, the first cases of infection with a novel coronavirus, SARS-CoV-2, were diagnosed. Currently, there is no effective antiviral treatment for COVID-19. To address this emerging problem, we focused on the SARS-CoV-2 main protease that constitutes one of the most attractive antiviral drug targets. We have synthesized a combinatorial library of fluorogenic substrates with glutamine in the P1 position. We used it to determine the substrate preferences of the SARS-CoV and SARS-CoV-2 main proteases. On the basis of these findings, we designed and synthesized a potent SARS-CoV-2 inhibitor (Ac-Abu-DTyr-Leu-Gln-VS, half-maximal effective concentration of 3.7 µM) and two activity-based probes, for one of which we determined the crystal structure of its complex with the SARS-CoV-2 Mpro. We visualized active SARS-CoV-2 Mpro in nasopharyngeal epithelial cells of patients suffering from COVID-19 infection. The results of our work provide a structural framework for the design of inhibitors as antiviral agents and/or diagnostic tests.


Subject(s)
Antiviral Agents/chemistry , COVID-19/diagnostic imaging , Coronavirus 3C Proteases/antagonists & inhibitors , Epithelial Cells/virology , Protease Inhibitors/chemistry , SARS-CoV-2/drug effects , Antiviral Agents/pharmacology , COVID-19/pathology , COVID-19/virology , Catalytic Domain , Combinatorial Chemistry Techniques , Coronavirus 3C Proteases/chemistry , Coronavirus 3C Proteases/genetics , Coronavirus 3C Proteases/metabolism , Crystallography, X-Ray , Drug Design , Epithelial Cells/ultrastructure , Fluorescent Dyes/chemistry , Gene Expression , Glutamine/chemistry , Humans , Models, Molecular , Nasopharynx/virology , Protease Inhibitors/pharmacology , Protein Binding , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Protein Interaction Domains and Motifs , SARS Virus/drug effects , SARS Virus/enzymology , SARS-CoV-2/enzymology , Substrate Specificity
11.
Int J Chron Obstruct Pulmon Dis ; 15: 2487-2494, 2020.
Article in English | MEDLINE | ID: covidwho-874299

ABSTRACT

Background: Social distancing and restriction measures during the COVID-19 epidemic may have impacts on medication availability and healthcare utilization for COPD patients, and thereby affect standard disease management. We aimed to investigate the change of respiratory symptoms, pharmacological treatment and healthcare utilization of COPD patients during the epidemic in Beijing, China. Methods: We conducted a single-center, cross-sectional survey performed at Peking University Third Hospital and recruited patients with COPD who were interviewed by phone call. Clinical data, including respiratory symptoms, pharmacological treatment, management and healthcare access before and during the COVID-19 epidemic from January 25 to April 25, 2020, were collected. Results: A total of 153 patients were enrolled for analysis. Before the epidemic, 81.7% (125/153) had long-term maintenance medication and ICS/LABA (60.8%) and LAMA (57.5%) were most commonly used. During the epidemic, 75.2% (115/153) maintained their pharmacological treatment and 6.5% (10/153) had to reduce or stop taking medications, with a slight decrease of patients taking ICS/LABA (53.6%) and LAMA (56.9%). Most of the patients [76.5% (117/153)] had a low symptom burden, with a CAT score <10 during the epidemic. Of 153 patients, 45 (29.4%) patients reported worsening of respiratory symptoms but only 15.6% (7/45) sought medical care in hospitals, while the remaining expressed concerns about cross-infection in the hospital (55.5%, 25/45) or had mild symptoms which were managed by themselves (28.8%, 13/45). Conclusion: During the COVID-19 epidemic in Beijing, most of our COPD patients maintained their long-term pharmacological treatment and had mild-to-moderate symptoms. Approximately, 30.0% of the patients experienced worsening of respiratory symptoms, but most of them did not seek medical care in the hospital due to concerns about cross-infection.


Subject(s)
Betacoronavirus , Coronavirus Infections/epidemiology , Health Services Accessibility , Patient Acceptance of Health Care , Pneumonia, Viral/epidemiology , Pulmonary Disease, Chronic Obstructive/therapy , Aged , Aged, 80 and over , Beijing , COVID-19 , Cross-Sectional Studies , Female , Humans , Male , Middle Aged , Pandemics , Pulmonary Disease, Chronic Obstructive/complications , SARS-CoV-2 , Self-Management
13.
J Med Chem ; 63(9): 4562-4578, 2020 05 14.
Article in English | MEDLINE | ID: covidwho-613484

ABSTRACT

The main protease of coronaviruses and the 3C protease of enteroviruses share a similar active-site architecture and a unique requirement for glutamine in the P1 position of the substrate. Because of their unique specificity and essential role in viral polyprotein processing, these proteases are suitable targets for the development of antiviral drugs. In order to obtain near-equipotent, broad-spectrum antivirals against alphacoronaviruses, betacoronaviruses, and enteroviruses, we pursued a structure-based design of peptidomimetic α-ketoamides as inhibitors of main and 3C proteases. Six crystal structures of protease-inhibitor complexes were determined as part of this study. Compounds synthesized were tested against the recombinant proteases as well as in viral replicons and virus-infected cell cultures; most of them were not cell-toxic. Optimization of the P2 substituent of the α-ketoamides proved crucial for achieving near-equipotency against the three virus genera. The best near-equipotent inhibitors, 11u (P2 = cyclopentylmethyl) and 11r (P2 = cyclohexylmethyl), display low-micromolar EC50 values against enteroviruses, alphacoronaviruses, and betacoronaviruses in cell cultures. In Huh7 cells, 11r exhibits three-digit picomolar activity against the Middle East Respiratory Syndrome coronavirus.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus/drug effects , Enterovirus/drug effects , Lactams/pharmacology , Peptidomimetics/pharmacology , Virus Replication/drug effects , 3C Viral Proteases , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/metabolism , Binding Sites , Cell Line, Tumor , Chlorocebus aethiops , Coronavirus/enzymology , Coronavirus 3C Proteases , Crystallography, X-Ray , Cysteine Endopeptidases/chemistry , Cysteine Endopeptidases/metabolism , Drug Design , Enterovirus/enzymology , Humans , Lactams/chemical synthesis , Lactams/metabolism , Peptidomimetics/chemical synthesis , Peptidomimetics/metabolism , Protease Inhibitors/chemical synthesis , Protease Inhibitors/metabolism , Protease Inhibitors/pharmacology , Protein Binding , Vero Cells , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/metabolism , Viral Proteins/antagonists & inhibitors , Viral Proteins/chemistry , Viral Proteins/metabolism
14.
Epidemiol Infect ; 148: e99, 2020 05 19.
Article in English | MEDLINE | ID: covidwho-306263

ABSTRACT

In late December 2019, patients of atypical pneumonia due to an unidentified microbial agent were reported in Wuhan, Hubei Province, China. Subsequently, a novel coronavirus was identified as the causative pathogen which was named SARS-CoV-2. As of 12 February 2020, more than 44 000 cases of SARS-CoV-2 infection have been confirmed in China and continue to expand. Provinces, municipalities and autonomous regions of China have launched first-level response to major public health emergencies one after another from 23 January 2020, which means restricting movement of people among provinces, municipalities and autonomous regions. The aim of this study was to explore the correlation between the migration scale index and the number of confirmed coronavirus disease 2019 (COVID-19) cases and to depict the effect of restricting population movement. In this study, Excel 2010 was used to demonstrate the temporal distribution at the day level and SPSS 23.0 was used to analyse the correlation between the migration scale index and the number of confirmed COVID-19 cases. We found that since 23 January 2020, Wuhan migration scale index has dropped significantly and since 26 January 2020, Hubei province migration scale index has dropped significantly. New confirmed COVID-19 cases per day in China except for Wuhan gradually increased since 24 January 2020, and showed a downward trend from 6 February 2020. New confirmed COVID-19 cases per day in China except for Hubei province gradually increased since 24 January 2020, and maintained at a high level from 24 January 2020 to 4 February 2020, then showed a downward trend. Wuhan migration scale index from 9 January to 22 January, 10 January to 23 January and 11 January to 24 January was correlated with the number of new confirmed COVID-19 cases per day in China except for Wuhan from 22 January to 4 February. Hubei province migration scale index from 10 January to 23 January and 11 January to 24 January was correlated with the number of new confirmed COVID-19 cases per day in China except for Hubei province from 22 January to 4 February. Our findings suggested that people who left Wuhan from 9 January to 22 January, and those who left Hubei province from 10 January to 24 January, led to the outbreak in the rest of China. The 'Wuhan lockdown' and the launching of the first-level response to this major public health emergency may have had a good effect on controlling the COVID-19 epidemic. Although new COVID-19 cases continued to be confirmed in China outside Wuhan and Hubei provinces, in our opinion, these are second-generation cases.


Subject(s)
Coronavirus Infections/epidemiology , Pneumonia, Viral/epidemiology , Travel/statistics & numerical data , Betacoronavirus , COVID-19 , China/epidemiology , Coronavirus Infections/diagnosis , Humans , Pandemics , Pneumonia, Viral/diagnosis , SARS-CoV-2 , Time
15.
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 , Coronavirus 3C Proteases , 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 , SARS-CoV-2 , Viral Nonstructural Proteins/metabolism , Virus Replication/drug effects
16.
Clin Transl Med ; 10(1): 28-35, 2020 Jan.
Article in English | MEDLINE | ID: covidwho-30703

ABSTRACT

A new coronavirus SARS-CoV-2 has caused outbreaks in multiple countries and the number of cases is rapidly increasing through human-to-human transmission. Clinical phenomes of patients with SARS-CoV-2 infection are critical in distinguishing it from other respiratory infections. The extent and characteristics of those phenomes varied depending on the severities of the infection, for example, beginning with fever or a mild cough, progressed with signs of pneumonia, and worsened with severe or even fatal respiratory difficulty in acute respiratory distress syndrome. We summarized clinical phenomes of 3795 patients with COVID-19 based on 80 published reports from the onset of outbreak to March 2020 to emphasize the importance and specificity of those phenomes in diagnosis and treatment of infection, and evaluate the impact on medical services. The data show that the incidence of male patients was higher than that of females and the level of C-reaction protein was increased as well as most patients' imaging included ground-glass opacity. Clinical phenomes of SARS-CoV-2 infection were compared with those of SARS-CoV and MERS-CoV infections. There is an urgent need to develop an artificial intelligence-based machine learning capacity to analyze and integrate radiomics- or imaging-based, patient-based, clinician-based, and molecular measurements-based data to fight the outbreak of COVID-19 and enable more efficient responses to unknown infections in future.

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