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1.
Front Microbiol ; 13: 829218, 2022.
Article in English | MEDLINE | ID: covidwho-1887105

ABSTRACT

The S2 subunit of infectious bronchitis virus (IBV) plays a critical role in the process of IBV infection. A comparison between the S2 subunit sequence of chicken embryo kidney cell (CEK) adapted virulent QX-like IBV strain SczyC30 (hereafter referred to as zy30) and its CEK-attenuated strain, SczyC100, revealed an N1038S substitution in S2 subunit and a 1154EQTRPKKSV1162 residue deletion in the C-terminus of the S2 subunit. In order to explore whether these two mutations are related to changes in the biological characteristics of IBV, we firstly constructed an infectious clone of zy30 using a bacterial artificial chromosome (BAC), which combines the transcription of infectious IBV genomic RNA in non-susceptible BHK-21 cells with the amplification of rescued virus rzy30 in CEK cells. Then, three recombinant viruses, including an rzy30S2-N1038S strain that contained the N1038S substitution, an rzy30S2-CT9△ strain that contained the 1154EQTRPKKSV1162 deletion, and an rzy30S2-N1038S-CT9△ strain that contained both mutations, were constructed using rescued virus rzy30 as the backbone. The results showed that each mutation did not significantly affect the replication titer in CEK cells but reduced pathogenicity in chickens, while in combination, the N1038S substitution and 1154EQTRPKKSV1162 deletion improved the proliferation efficiency in CEK cells and reduced pathogenicity, compared to rzy30 strain. The contribution made by the 1154EQTRPKKSV1162 deletion in reducing pathogenicity was higher than that of N1038S substitution. Our results revealed that the N1038S substitution and 1154EQTRPKKSV1162 deletion in S2 subunit were deeply involved in the replication efficiency of IBV and contributed to reduction of viral pathogenicity.

2.
Pharmaceutics ; 14(3)2022 Mar 10.
Article in English | MEDLINE | ID: covidwho-1742580

ABSTRACT

Matrine (MAR), oxymatrine (OMAR), and sophoridine (SPD) are natural alkaloids with varying biological activities; matrine was recently used for the treatment of coronavirus disease 2019 (COVID-19). However, the short half-lives and rapid elimination of these matrine-type alkaloids would lead to low oral bioavailability and serious side effects. Herein, resveratrol (RES) was selected as a co-former to prepare their co-amorphous systems to improve the therapeutic index. The formation of co-amorphous MAR-RES, OMAR-RES, and SPD-RES was established through powder X-ray diffraction and modulated temperature differential scanning calorimetry. Furthermore, Fourier transform infrared spectroscopy and NMR studies revealed the strong molecular interactions between resveratrol and these alkaloids, especially OMAR-RES. Matrine, oxymatrine, and sophoridine in the co-amorphous systems showed sustained release behaviors in the dissolution experiments, due to the recrystallization of resveratrol on the surface of co-amorphous drugs. The three co-amorphous systems exhibited excellent physicochemical stability under high relative humidity conditions. Our study not only showed that minor structural changes of active pharmaceutical ingredients may have distinct molecular interactions with the co-former, but also discovered a new type of sustained release mechanism for co-amorphous drugs. This promising co-amorphous drug approach may present a unique opportunity for repurposing these very promising drugs against COVID-19.

3.
Biomedicines ; 10(1)2021 Dec 21.
Article in English | MEDLINE | ID: covidwho-1638079

ABSTRACT

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease affecting about 25% of world population, while there are still no approved targeted therapies. Although platensimycin (PTM) was first discovered to be a broad-spectrum antibiotic, it was also effective against type II diabetes in animal models due to its ability to inhibit both bacterial and mammalian fatty acid synthases (FASN). Herein, we report the pharmacological effect and potential mode of action of PTM against NAFLD in a Western diet/CCI4-induced mouse model and a free fatty acids (FFAs)-induced HepG2 cell model. The proper dose of PTM and its liposome-based nano-formulations not only significantly attenuated the Western diet-induced weight gain and the levels of plasma total triglycerides and glucose, but reduced liver steatosis in mice according to histological analyses. Western blotting analysis showed a reduced protein level of FASN in the mouse liver, suggesting that PTM intervened in the development of NAFLD through FASN inhibition. PTM reduced both the protein and mRNA levels of FASN in FFAs-induced HepG2 cells, as well as the expression of several key proteins in lipogenesis, including sterol regulatory element binding protein-1, acetyl-CoA carboxylase, and stearoyl-CoA desaturase. The expression of lipid oxidation-related genes, including peroxisome proliferator activated receptor α and acyl-CoA oxidase 1, was significantly elevated. In conclusion, our study supports the reposition of PTM to intervene in NAFLD progression, since it could effectively inhibit de novo lipogenesis.

4.
PLoS Negl Trop Dis ; 16(1): e0010048, 2022 01.
Article in English | MEDLINE | ID: covidwho-1606114

ABSTRACT

BACKGROUND: The first community transmission of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Delta variant of concern (VOC) in Guangzhou, China occurred between May and June 2021. Herein, we describe the epidemiological characteristics of this outbreak and evaluate the implemented containment measures against this outbreak. METHODOLOGY/PRINCIPAL FINDINGS: Guangzhou Center for Disease Control and Prevention provided the data on SARS-CoV-2 infections reported between 21 May and 24 June 2021. We estimated the incubation period distribution by fitting a gamma distribution to the data, while the serial interval distribution was estimated by fitting a normal distribution. The instantaneous effective reproductive number (Rt) was estimated to reflect the transmissibility of SARS-CoV-2. Clinical severity was compared for cases with different vaccination statuses using an ordinal regression model after controlling for age. Of the reported local cases, 7/153 (4.6%) were asymptomatic. The median incubation period was 6.02 (95% confidence interval [CI]: 5.42-6.71) days and the means of serial intervals decreased from 5.19 (95% CI: 4.29-6.11) to 3.78 (95% CI: 2.74-4.81) days. The incubation period increased with age (P<0.001). A hierarchical prevention and control strategy against COVID-19 was implemented in Guangzhou, with Rt decreasing from 6.83 (95% credible interval [CrI]: 3.98-10.44) for the 7-day time window ending on 27 May 2021 to below 1 for the time window ending on 8 June and thereafter. Individuals with partial or full vaccination schedules with BBIBP-CorV or CoronaVac accounted for 15.3% of the COVID-19 cases. Clinical symptoms were milder in partially or fully vaccinated cases than in unvaccinated cases (odds ratio [OR] = 0.26 [95% CI: 0.07-0.94]). CONCLUSIONS/SIGNIFICANCE: The hierarchical prevention and control strategy against COVID-19 in Guangzhou was timely and effective. Authorised inactivated vaccines are likely to contribute to reducing the probability of developing severe disease. Our findings have important implications for the containment of COVID-19.


Subject(s)
COVID-19 Vaccines/therapeutic use , COVID-19/epidemiology , COVID-19/prevention & control , Communicable Disease Control/methods , SARS-CoV-2/isolation & purification , Adult , Aged , Basic Reproduction Number , COVID-19/transmission , China/epidemiology , Female , Humans , Male , Middle Aged , Primary Prevention/methods , Severity of Illness Index , Vaccination/statistics & numerical data , Young Adult
5.
Biomaterials ; 280: 121249, 2022 01.
Article in English | MEDLINE | ID: covidwho-1507702

ABSTRACT

The emergence and spread of antibiotic resistance is one of the biggest challenges in public health. There is an urgent need to discover novel agents against the occurrence of multidrug-resistant bacteria, such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci. The drug-resistant pathogens are able to grow and persist in infected sites, including biofilms, phagosomes, or phagolysosomes, which are more difficult to eradicate than planktonic ones and also foster the development of drug resistance. For years, various nano-antibacterial agents have been developed in the forms of antibiotic nanocarriers. Inorganic nanoparticles with intrinsic antibacterial activity and inert nanoparticles assisted by external stimuli, including heat, photon, magnetism, or sound, have also been discovered. Many of these strategies are designed to target the unique microenvironment of bacterial infections, which have shown potent antibacterial effects in vitro and in vivo. This review summarizes ongoing efforts on antibacterial nanotherapeutic strategies related to bacterial infection microenvironments, including targeted antibacterial therapy and responsive antibiotic delivery systems. Several grand challenges and future directions for the development and translation of effective nano-antibacterial agents are also discussed. The development of innovative nano-antibacterial agents could provide powerful weapons against drug-resistant bacteria in systemic or local bacterial infections in the foreseeable future.


Subject(s)
Bacterial Infections , Methicillin-Resistant Staphylococcus aureus , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Bacterial Infections/drug therapy , Biofilms , Drug Resistance, Multiple, Bacterial , Humans , Microbial Sensitivity Tests
6.
Comput Biol Chem ; 95: 107599, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1487668

ABSTRACT

Novel coronavirus disease 2019 (COVID-19) is a global pandemic caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), which can be transmitted from person to person. As of September 21, 2021, over 228 million cases were diagnosed as COVID-19 infection in more than 200 countries and regions worldwide. The death toll is more than 4.69 million and the mortality rate has reached about 2.05% as it has gradually become a global plague, and the numbers are growing. Therefore, it is important to gain a deeper understanding of the genome and protein characteristics, clinical diagnostics, pathogenic mechanisms, and the development of antiviral drugs and vaccines against the novel coronavirus to deal with the COVID-19 pandemic. The traditional biology technologies are limited for COVID-19-related studies to understand the pandemic happening. Bioinformatics is the application of computational methods and analytical tools in the field of biological research which has obvious advantages in predicting the structure, product, function, and evolution of unknown genes and proteins, and in screening drugs and vaccines from a large amount of sequence information. Here, we comprehensively summarized several of the most important methods and applications relating to COVID-19 based on currently available reports of bioinformatics technologies, focusing on future research for overcoming the virus pandemic. Based on the next-generation sequencing (NGS) and third-generation sequencing (TGS) technology, not only virus can be detected, but also high quality SARS-CoV-2 genome could be obtained quickly. The emergence of data of genome sequences, variants, haplotypes of SARS-CoV-2 help us to understand genome and protein structure, variant calling, mutation, and other biological characteristics. After sequencing alignment and phylogenetic analysis, the bat may be the natural host of the novel coronavirus. Single-cell RNA sequencing provide abundant resource for discovering the mechanism of immune response induced by COVID-19. As an entry receptor, angiotensin-converting enzyme 2 (ACE2) can be used as a potential drug target to treat COVID-19. Molecular dynamics simulation, molecular docking and artificial intelligence (AI) technology of bioinformatics methods based on drug databases for SARS-CoV-2 can accelerate the development of drugs. Meanwhile, computational approaches are helpful to identify suitable vaccines to prevent COVID-19 infection through reverse vaccinology, Immunoinformatics and structural vaccinology.


Subject(s)
COVID-19/epidemiology , Computational Biology/methods , Pandemics , Antiviral Agents/therapeutic use , Artificial Intelligence , COVID-19/drug therapy , COVID-19/virology , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , SARS-CoV-2/isolation & purification
7.
Acta Pharmacol Sin ; 42(11): 1913-1920, 2021 11.
Article in English | MEDLINE | ID: covidwho-1437673

ABSTRACT

Sepsis is a dysregulated immune response to infection and potentially leads to life-threatening organ dysfunction, which is often seen in serious Covid-19 patients. Disulfiram (DSF), an old drug that has been used to treat alcohol addiction for decades, has recently been identified as a potent inhibitor of the gasdermin D (GSDMD)-induced pore formation that causes pyroptosis and inflammatory cytokine release. Therefore, DSF represents a promising therapeutic for the treatment of inflammatory disorders. Lactoferrin (LF) is a multifunctional glycoprotein with potent antibacterial and anti-inflammatory activities that acts by neutralizing circulating endotoxins and activating cellular responses. In addition, LF has been well exploited as a drug nanocarrier and targeting ligands. In this study, we developed a DSF-LF nanoparticulate system (DSF-LF NP) for combining the immunosuppressive activities of both DSF and LF. DSF-LF NPs could effectively block pyroptosis and inflammatory cytokine release from macrophages. Treatment with DSF-LF NPs showed remarkable therapeutic effects on lipopolysaccharide (LPS)-induced sepsis. In addition, this therapeutic strategy was also applied to treat ulcerative colitis (UC), and substantial treatment efficacy was achieved in a murine colitis model. The underlying mode of action of these DSF-LF-NPs may contribute to efficiently suppressing macrophage-mediated inflammatory responses and ameliorating the complications caused by sepsis and UC. As macrophage pyroptosis plays a pivotal role in inflammation, this safe and effective biomimetic nanomedicine may offer a versatile therapeutic strategy for treating various inflammatory diseases by repurposing DSF.


Subject(s)
COVID-19 , Colitis, Ulcerative , Disulfiram/pharmacokinetics , Lactoferrin , Systemic Inflammatory Response Syndrome , Acetaldehyde Dehydrogenase Inhibitors/pharmacology , Animals , Anti-Inflammatory Agents/pharmacology , Biomimetic Materials/pharmacology , COVID-19/drug therapy , COVID-19/immunology , Colitis, Ulcerative/drug therapy , Colitis, Ulcerative/immunology , Disease Models, Animal , Disulfiram/pharmacology , Drug Carriers/pharmacology , Humans , Immunosuppressive Agents/pharmacology , Lactoferrin/metabolism , Lactoferrin/pharmacology , Lipopolysaccharides/immunology , Macrophages/drug effects , Macrophages/immunology , Mice , Mice, Inbred C57BL , Nanoparticles/therapeutic use , Pyroptosis/drug effects , SARS-CoV-2 , Systemic Inflammatory Response Syndrome/drug therapy , Systemic Inflammatory Response Syndrome/immunology , Systemic Inflammatory Response Syndrome/metabolism , Treatment Outcome
8.
Journal of Travel Medicine ; 27(8), 2020.
Article in English | CAB Abstracts | ID: covidwho-1410186

ABSTRACT

The coronavirus disease 2019 is a global public health emergency that has been caused by the SARS-CoV-2 virus. Since it has a higher number of cases than SARS, it is considered a more infectious disease. The prevalence of COVID-19 in air passengers increases when the pandemic is over. Due to the rapid urbanization and the establishment of a transportation hub in China, the number of COVID-19 cases in Guangzhou has been reduced to low levels since early 2020. However, the resurgence risk remains significant. This study aims to provide an overview of the policies and control measures related to the entry of COVID-19 cases from abroad. After the SARS-CoV-2 outbreak in Guangdong was widely publicized, the local government issued a series of measures to contain its spread. All travellers and residents who entered the city after passing through immigration checkpoints were required to submit a RT-PCR test. From March to July 2020, a total of 268 COVID-19 cases were confirmed in China. Most of the imported cases were male and were engaged in commercial activities. The majority of the cases originated from Europe and Asia. Out of the 85 imported cases identified, 73.5% were detected during the customs inspection and 19.0% were under centralized quarantine. The remaining cases were confirmed during a consultation with a healthcare professional. Twenty-four samples were collected from the living areas of 12 imported cases, which indicated that SARS-CoV-2 was prevalent in these areas. The majority of the positive samples were from household objects such as door handle, sink, and remote control.

9.
Emerg Microbes Infect ; 10(1): 1751-1759, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1393119

ABSTRACT

The effectiveness of inactivated SARS-CoV-2 vaccines against the Delta variant, which has been associated with greater transmissibility and virulence, remains unclear. We conducted a test-negative case-control study to explore the vaccine effectiveness (VE) in real-world settings. We recruited participants aged 18-59 years who consisted of SARS-CoV-2 test-positive cases (n = 74) and test-negative controls (n = 292) during the outbreak of the Delta variant in May 2021 in Guangzhou city, China. Vaccination status was compared to estimate The VE of SARS-CoV-2 inactivated vaccines. A single dose of inactivated SARS-CoV-2 vaccine yielded the VE of only 13.8%. After adjusting for age and sex, the overall VE for two-dose vaccination was 59.0% (95% confidence interval: 16.0% to 81.6%) against coronavirus disease 2019 (COVID-19) and 70.2% (95% confidence interval: 29.6-89.3%) against moderate COVID-19 and 100% against severe COVID-19 which might be overestimated due to the small sample size. The VE of two-dose vaccination against COVID-19 reached 72.5% among participants aged 40-59 years, and was higher in females than in males against COVID-19 and moderate diseases. While single dose vaccination was not sufficiently protective, the two-dose dosing scheme of the inactivated vaccines was effective against the Delta variant infection in real-world settings, with the estimated efficacy exceeding the World Health Organization minimal threshold of 50%.


Subject(s)
COVID-19 Vaccines/standards , COVID-19/prevention & control , SARS-CoV-2/genetics , Adolescent , Adult , Age Distribution , COVID-19/classification , COVID-19 Vaccines/administration & dosage , Case-Control Studies , China , Disease Outbreaks , Female , Genetic Variation , Humans , Male , Middle Aged , Vaccines, Inactivated/administration & dosage , Vaccines, Inactivated/standards , Young Adult
10.
EBioMedicine ; 69: 103439, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1275277

ABSTRACT

BACKGROUND: COVID-19 has been associated with Interstitial Lung Disease features. The immune transcriptomic overlap between Idiopathic Pulmonary Fibrosis (IPF) and COVID-19 has not been investigated. METHODS: we analyzed blood transcript levels of 50 genes known to predict IPF mortality in three COVID-19 and two IPF cohorts. The Scoring Algorithm of Molecular Subphenotypes (SAMS) was applied to distinguish high versus low-risk profiles in all cohorts. SAMS cutoffs derived from the COVID-19 Discovery cohort were used to predict intensive care unit (ICU) status, need for mechanical ventilation, and in-hospital mortality in the COVID-19 Validation cohort. A COVID-19 Single-cell RNA-sequencing cohort was used to identify the cellular sources of the 50-gene risk profiles. The same COVID-19 SAMS cutoffs were used to predict mortality in the IPF cohorts. FINDINGS: 50-gene risk profiles discriminated severe from mild COVID-19 in the Discovery cohort (P = 0·015) and predicted ICU admission, need for mechanical ventilation, and in-hospital mortality (AUC: 0·77, 0·75, and 0·74, respectively, P < 0·001) in the COVID-19 Validation cohort. In COVID-19, 50-gene expressing cells with a high-risk profile included monocytes, dendritic cells, and neutrophils, while low-risk profile-expressing cells included CD4+, CD8+ T lymphocytes, IgG producing plasmablasts, B cells, NK, and gamma/delta T cells. Same COVID-19 SAMS cutoffs were also predictive of mortality in the University of Chicago (HR:5·26, 95%CI:1·81-15·27, P = 0·0013) and Imperial College of London (HR:4·31, 95%CI:1·81-10·23, P = 0·0016) IPF cohorts. INTERPRETATION: 50-gene risk profiles in peripheral blood predict COVID-19 and IPF outcomes. The cellular sources of these gene expression changes suggest common innate and adaptive immune responses in both diseases. FUNDING: This work was supported in part by National Institute for Health Research Clinician Scientist Fellowship NIHR: CS-2013-13-017 (TMM); Action for Pulmonary Fibrosis Mike Bray fellowship (PLM); The National Heart, Lung, and Blood Institute (NHLBI) through award K01-HL-130704 (AJ); The University of South Florida (USF) Academic Support Fund and the USF Foundation, Ubben Fibrosis Fund (JHM).


Subject(s)
COVID-19/genetics , Transcriptome , Adult , Aged , Biomarkers/blood , COVID-19/blood , COVID-19/mortality , Female , Hospital Mortality , Humans , Male , Middle Aged , Survival Analysis
11.
Angewandte Chemie ; 133(18):9873-9886, 2021.
Article in English | ProQuest Central | ID: covidwho-1193057

ABSTRACT

The mainstream approach to antiviral drugs against COVID‐19 is to focus on key stages of the SARS‐CoV‐2 life cycle. The vast majority of candidates under investigation are repurposed from agents of other indications. Understanding protein–inhibitor interactions at the molecular scale will provide crucial insights for drug discovery to stop this pandemic. In this article, we summarize and analyze the most recent structural data on several viral targets in the presence of promising inhibitors for COVID‐19 in the context of the perspective of modes of action (MOA) to unravel insightful mechanistic features with atomistic resolution. The targets include spike glycoprotein and various host proteases mediating the entry of the virus into the cells, viral chymotrypsin‐ and papain‐like proteases, and RNA‐dependent RNA polymerase. The main purpose of this review is to present detailed MOA analysis to inspire fresh ideas for both de novo drug design and optimization of known scaffolds to combat COVID‐19.

12.
Innovation (N Y) ; 1(3): 100046, 2020 Nov 25.
Article in English | MEDLINE | ID: covidwho-1164617

ABSTRACT

[This corrects the article DOI: 10.1016/j.xinn.2020.100028.].

16.
Stem Cells Int ; 2020: 8861407, 2020.
Article in English | MEDLINE | ID: covidwho-952055

ABSTRACT

Mesenchymal stem cells (MSCs) may improve the treatment of acute respiratory distress syndrome (ARDS). However, few studies have investigated the effects of mechanically stretched -MSCs (MS-MSCs) in in vitro models of ARDS. The aim of this study was to evaluate the potential therapeutic effects of MS-MSCs on pulmonary microvascular endothelium barrier injuries induced by LPS. We introduced a cocultured model of pulmonary microvascular endothelial cell (EC) and MSC medium obtained from MSCs with or without mechanical stretch. We found that Wright-Giemsa staining revealed that MSC morphology changed significantly and cell plasma shrank separately after mechanical stretch. Cell proliferation of the MS-MSC groups was much lower than the untreated MSC group; expression of cell surface markers did not change significantly. Compared to the medium from untreated MSCs, inflammatory factors elevated statistically in the medium from MS-MSCs. Moreover, the paracellular permeability of endothelial cells treated with LPS was restored with a medium from MS-MSCs, while LPS-induced EC apoptosis decreased. In addition, protective effects on the remodeling of intercellular junctions were observed when compared to LPS-treated endothelial cells. These data demonstrated that the MS-MSC groups had potential therapeutic effects on the LPS-treated ECs; these results might be useful in the treatment of ARDS.

17.
J Infect Chemother ; 26(5): 523-526, 2020 May.
Article in English | MEDLINE | ID: covidwho-828066

ABSTRACT

Transmissible gastroenteritis virus (TGEV) and porcine epidemic diarrhea virus (PEDV) are the main pathogens causing viral diarrhea in pig, mixed infections of these two viruses are very common in intensive pig rearing. However, there is a lack of a method to simultaneously detect and distinguish PEDV and TGEV in preclinical levels. In this study, we aimed to establish a dual ultrasensitive nanoparticle DNA probe-based PCR assay (dual UNDP-PCR) based on functionalized magnetic bead enrichment and specific nano-technology amplification for simultaneous detection and distinguish diagnosis of PEDV and TGEV. The detection limit of dual UNDP-PCR for single or multiple infections of PEDV and TGEV is 25 copies/g, which is 400 times more sensitive than the currently known duplex RT-PCR, showing better specificity and sensitivity without cross-reaction with other viruses. For pre-clinical fecal samples, the dual UNDP-PCR showed a markedly higher positive detection rate (52.08%) than conventional duplex RT-PCR (13.21%), can rapidly and accurately identify targeted pathogens whenever simple virus infection or co-infection. In summary, this study provides a technique for detecting and distinguishing PEDV and TGEV in preclinical levels, which is high sensitivity, specificity, repeatability, low cost and broad application prospect.


Subject(s)
DNA Probes/chemistry , Gastroenteritis, Transmissible, of Swine/diagnosis , Nanoparticles/chemistry , Porcine epidemic diarrhea virus/isolation & purification , Reverse Transcriptase Polymerase Chain Reaction/veterinary , Transmissible gastroenteritis virus/isolation & purification , Animals , DNA Probes/genetics , Diarrhea/veterinary , Diarrhea/virology , Feces/virology , Gastroenteritis, Transmissible, of Swine/virology , Limit of Detection , Magnets , Porcine epidemic diarrhea virus/genetics , RNA, Viral/genetics , RNA, Viral/isolation & purification , Reproducibility of Results , Reverse Transcriptase Polymerase Chain Reaction/methods , Sensitivity and Specificity , Swine , Swine Diseases/diagnosis , Swine Diseases/virology , Transmissible gastroenteritis virus/genetics
18.
Innovation (N Y) ; 1(2): 100028, 2020 08 28.
Article in English | MEDLINE | ID: covidwho-720752

ABSTRACT

Since the outbreak of COVID-19, many randomized controlled trials have been launched to test the efficacy of promising treatments. These trials will offer great promise for future treatment. However, a public health emergency calls for a balance between gathering sound evidence and granting therapeutic access to promising trial drugs as widely as possible. In an electronic survey, we found that 3.9% of the participants preferred to receive an unproven trial drug directly in the hypothetical scenario of mild COVID-19 infection. This percentage increased drastically to 31.1% and 54.2% in the hypothetical scenario of severe and extremely severe infection, respectively. Our survey indicates a likelihood of substantial receptivity of trial drugs among actual patients in severe conditions. From the perspective of deontological ethics, a trial can only be approved when potential benefits of the investigational treatment are presumed to outweigh risks, so compassionate or off-label use of investigational therapies merits evaluation.

19.
Nature ; 586(7830): 572-577, 2020 10.
Article in English | MEDLINE | ID: covidwho-691301

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a respiratory disease called coronavirus disease 2019 (COVID-19), the spread of which has led to a pandemic. An effective preventive vaccine against this virus is urgently needed. As an essential step during infection, SARS-CoV-2 uses the receptor-binding domain (RBD) of the spike protein to engage with the receptor angiotensin-converting enzyme 2 (ACE2) on host cells1,2. Here we show that a recombinant vaccine that comprises residues 319-545 of the RBD of the spike protein induces a potent functional antibody response in immunized mice, rabbits and non-human primates (Macaca mulatta) as early as 7 or 14 days after the injection of a single vaccine dose. The sera from the immunized animals blocked the binding of the RBD to ACE2, which is expressed on the cell surface, and neutralized infection with a SARS-CoV-2 pseudovirus and live SARS-CoV-2 in vitro. Notably, vaccination also provided protection in non-human primates to an in vivo challenge with SARS-CoV-2. We found increased levels of RBD-specific antibodies in the sera of patients with COVID-19. We show that several immune pathways and CD4 T lymphocytes are involved in the induction of the vaccine antibody response. Our findings highlight the importance of the RBD domain in the design of SARS-CoV-2 vaccines and provide a rationale for the development of a protective vaccine through the induction of antibodies against the RBD domain.


Subject(s)
Antibodies, Viral/immunology , Betacoronavirus/immunology , Coronavirus Infections/immunology , Coronavirus Infections/prevention & control , Pandemics/prevention & control , Pneumonia, Viral/immunology , Pneumonia, Viral/prevention & control , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology , Viral Vaccines/immunology , Animals , Antibodies, Neutralizing/immunology , COVID-19 , COVID-19 Vaccines , Humans , Macaca mulatta/immunology , Macaca mulatta/virology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Models, Animal , Models, Molecular , Protein Domains , SARS-CoV-2 , Serum/immunology , Spleen/cytology , Spleen/immunology , T-Lymphocytes/immunology , Vaccination
20.
Angew Chem Int Ed Engl ; 60(18): 9789-9802, 2021 04 26.
Article in English | MEDLINE | ID: covidwho-689094

ABSTRACT

The mainstream approach to antiviral drugs against COVID-19 is to focus on key stages of the SARS-CoV-2 life cycle. The vast majority of candidates under investigation are repurposed from agents of other indications. Understanding protein-inhibitor interactions at the molecular scale will provide crucial insights for drug discovery to stop this pandemic. In this article, we summarize and analyze the most recent structural data on several viral targets in the presence of promising inhibitors for COVID-19 in the context of the perspective of modes of action (MOA) to unravel insightful mechanistic features with atomistic resolution. The targets include spike glycoprotein and various host proteases mediating the entry of the virus into the cells, viral chymotrypsin- and papain-like proteases, and RNA-dependent RNA polymerase. The main purpose of this review is to present detailed MOA analysis to inspire fresh ideas for both de novo drug design and optimization of known scaffolds to combat COVID-19.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Drug Discovery , SARS-CoV-2/drug effects , Small Molecule Libraries/pharmacology , Antiviral Agents/chemistry , COVID-19/metabolism , Drug Design , Humans , Molecular Docking Simulation , Molecular Targeted Therapy , SARS-CoV-2/physiology , Small Molecule Libraries/chemistry , Virus Internalization/drug effects
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