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1.
European Journal of Medicinal Chemistry ; : 114426, 2022.
Article in English | ScienceDirect | ID: covidwho-1821218

ABSTRACT

The COVID-19 pandemic generates a global threat to public health and continuously emerging SARS-CoV-2 variants bring a great challenge to the development of both vaccines and antiviral agents. In this study, we identified UA-18 and its optimized analog UA-30 via the hit-to-lead strategy as novel SARS-CoV-2 fusion inhibitors. The lead compound UA-30 showed potent antiviral activity against infectious SARS-CoV-2 (wuhan-HU-1 variant) in Vero-E6 cells and was also effective against infection of diverse pseudotyped SARS-CoV-2 variants with mutations in the S protein including the Omicron and Delta variants. More importantly, UA-30 might target the cavity between S1 and S2 subunits to stabilize the prefusion state of the SARS-CoV-2 S protein, thus leading to interfering with virus-cell membrane fusion. This study offers a set of novel SARS-CoV-2 fusion inhibitors against SARS-CoV-2 and its variants based on the 3-O-β-chacotriosyl UA skeleton.

2.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-329660

ABSTRACT

Following Delta, Omicron variant triggered a new wave of SARS-CoV-2 infection globally, adaptive evolution of the virus may not stop, the development of broad-spectrum antivirals is still urgent. We previously developed two hetero-bivalent nanobodies with potent neutralization against original WT SARS-CoV-2, termed aRBD-2-5 and aRBD-2-7, by fusing aRBD-2 with aRBD-5 or aRBD-7, respectively. Here, we resolved crystal structures of these nanobodies in complex with RBD, and found the epitope of aRBD-2 differs from that of aRBD-5, aRBD-7. aRBD-2 binds to a conserved epitope which renders its binding activity to all variants of concern (VOCs) including Omicron. Interestingly, although monovalent aRBD-5 and aRBD-7 lost binding to some variants, they effectively improved the overall affinity when transformed into the hetero-bivalent form after being fused with aRBD-2. Consistent with the high binding affinities, aRBD-2-5-Fc and aRBD-2-7-Fc exhibited ultra-potent neutralization to all five VOCs;particularly, aRBD-2-5-Fc neutralized authentic virus of Beta, Delta and Omicron with the IC50 of 5.98~9.65 ng/mL or 54.3~87.6 pM. Importantly, aRBD-2-5-Fc provided in vivo prophylactic protection for mice against WT and mouse-adapted SARS-CoV-2, and provided full protection against Omicron in hamster model when administrated either prophylactically or therapeutically. Taken together, we found a conserved epitope on RBD, and hetero-bivalent nanobodies had increased affinity for VOCs over its monovalent form, and provided potent and broad-spectrum protection both in vitro and in vivo against all tested major variants, and potentially future emerging variants. Our strategy provides a new solution in the development of therapeutic antibodies for COVID-19 caused by newly emergent VOCs.

3.
Small Science ; n/a(n/a):2100124, 2022.
Article in English | Wiley | ID: covidwho-1739237

ABSTRACT

The current COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is an enormous threat to public health. The SARS-CoV-2 3C-like protease (3CLpro), which is critical for viral replication and transcription, has been recognized as an ideal drug target. Herein, it is identified that three herbal compounds, Salvianolic acid A (SAA), (?)-Epigallocatechin gallate (EGCG), and Oridonin, directly inhibit the activity of SARS-CoV-2 3CLpro. Further, blocking SARS-CoV-2 infectivity by Oridonin is confirmed in cell-based experiments. By solving the crystal structure of 3CLpro in complex with Oridonin and comparing it to that of other ligands with 3CLpro, it is identified that Oridonin binds at the 3CLpro catalytic site by forming a C?S covalent bond, which is confirmed by mass spectrometry and kinetic study, blocking substrate binding through a nonpeptidomimetic covalent binding mode. Thus, Oridonin is a novel candidate to develop a new antiviral treatment for COVID-19.

4.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-329417

ABSTRACT

SARS-CoV-2 has infected more than 400 million people around the globe and caused millions of deaths. Since its identification in November 2021, Omicron, a highly transmissible variant, has become the dominant variant in most countries. Omicron highly mutated spike protein, the main target of vaccine development, significantly compromises the immune protection from current vaccination. We develop an mRNA vaccine (SOmicron-6P) based on an Omicron-specific sequence. In mice, SOmicron-6P shows superior neutralizing antibodies inducing abilities to a clinically approved inactivated virus vaccine, a clinically approved protein subunit vaccine, and an mRNA vaccine (SWT-2P) with the same sequence of BNT162b2 RNA. Significantly, SOmicron-6P induces a 14.4~27.7-fold and a 28.3~50.3-fold increase of neutralizing activity against the pseudovirus of Omicron and authentic Omicron compared to SWT-2P, respectively. In addition, two doses SOmicron-6P significantly protects Syrian hamsters against challenge with SARS-CoV-2 Omicron variant and elicits high titers of nAbs in a dose-dependent manner in macaques. Our results suggest that SOmicron-6P offers advantages over current vaccines, and it will be helpful for those with weak immunity.

5.
Nat Immunol ; 23(3): 423-430, 2022 03.
Article in English | MEDLINE | ID: covidwho-1713201

ABSTRACT

The global severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic requires effective therapies against coronavirus disease 2019 (COVID-19), and neutralizing antibodies are a promising therapy. A noncompeting pair of human neutralizing antibodies (B38 and H4) blocking SARS-CoV-2 binding to its receptor, ACE2, have been described previously. Here, we develop bsAb15, a bispecific monoclonal antibody (bsAb) based on B38 and H4. bsAb15 has greater neutralizing efficiency than these parental antibodies, results in less selective pressure and retains neutralizing ability to most SARS-CoV-2 variants of concern (with more potent neutralizing activity against the Delta variant). We also selected for escape mutants of the two parental mAbs, a mAb cocktail and bsAb15, demonstrating that bsAb15 can efficiently neutralize all single-mAb escape mutants. Furthermore, prophylactic and therapeutic application of bsAb15 reduced the viral titer in infected nonhuman primates and human ACE2 transgenic mice. Therefore, this bsAb is a feasible and effective strategy to treat and prevent severe COVID-19.


Subject(s)
Antibodies, Bispecific/immunology , Antibodies, Monoclonal/immunology , Antibodies, Viral/immunology , SARS-CoV-2/immunology , Animals , Antibodies, Bispecific/chemistry , Antibodies, Bispecific/genetics , Antibodies, Monoclonal/chemistry , Antibodies, Monoclonal/genetics , Antibodies, Neutralizing/genetics , Antibodies, Neutralizing/immunology , Antibodies, Viral/chemistry , Antibodies, Viral/genetics , COVID-19/immunology , COVID-19/pathology , COVID-19/prevention & control , COVID-19/virology , Cloning, Molecular , Disease Models, Animal , Dose-Response Relationship, Immunologic , Epitopes , Humans , Macaca mulatta , Mice , Neutralization Tests , Protein Engineering/methods , Structure-Activity Relationship
6.
EuropePMC;
Preprint in English | EuropePMC | ID: ppcovidwho-328809

ABSTRACT

A SVEIR SARS-CoV-2 Omicron variant model is proposed to provide some insight to coordinate non-pharmaceutical interventions(NPIs) and vaccination. Mathematically, we define the basic reproduction number R0 and the effective reproduction number Re to measure the infection potential of Omicron variant and formulate a optimal disease control strategy. Our inversion results imply that the sick period of Omicron variant in the United States is longer than that of Delta variant in Indian;The decreasing of the infectious period of the infection with infectiousness implies that the risk of hospitalization is reduced;but the increasing period of the infection with non-infectiousness signifies that Omicron variant lengthens the period of nucleic acid test being negative;Optimistically, Omicron's death rate is only a quarter of Delta's. Moreover, we forecast that the cumulative cases will exceed 100 million in the United States on 28 February, 2022 and the daily confirmed cases will reach a peak on 2 February, 2022. The results of parameters sensitivity analysis imply that NPIs is helpful to reduce the number of confirmed cases. Especially, NPIs are indispensable even if all the people were vaccinated when the efficiency of vaccine is relatively low. By simulating the relation ships of the effective reproduction number Re , the vaccination rate and the efficacy of vaccine, we find that it is impossible to achieve the herd immunity without NPIs while the efficiency of vaccine is lower than 88.7%. Therefore, the herd immunity area is defined by the evolution of relationships between the vaccination rate and the efficacy of vaccine. Finally, we present that the disease-induced mortality rate demonstrates the periodic oscillation and an almost periodic function is deduced to match the curve. A discussion completes the paper.AMS Subject Classification (2020): 34A34;34D20;92D30

7.
EuropePMC;
Preprint in English | EuropePMC | ID: ppcovidwho-327476

ABSTRACT

Aim The objective of this analysis was to assess the association of excess COVID-19 mortality with regulation enforcement and vaccination rate in selected countries. Methods This analysis included 50 countries pertinent to the WHO European Region, in addition to USA and Canada. Excess mortality and vaccination data were retrieved from “Our World In Data” database, while regulation implementation was measured from a well-respected, standardized measure. Outpatient visits were also included in the analysis. Multiple linear regression was used to assess the independent association between excess mortality and each covariate. Results Excess mortality increased by 4.1/100 000 for every percent decrease in vaccination rate and with 6/100 000 for every decreased unit in the regulatory implementation score a country achieved in the Rule of Law Index. Conclusion Degree of regulation enforcement, likely including public health measure enforcement, may be an important factor in controlling COVID-19’s deleterious health impacts.

8.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-323717

ABSTRACT

Background: At the beginning of the outbreak of coronavirus infected disease 2019 (COVID-19), children in Wuhan were experiencing an extremely strong influenza A epidemic. This study is aimed to explore the epidemic dynamics characteristics of children with influenza A and its correlation with the early stage spread of COVID-19 in Wuhan. Methods: : This is a retrospective single-center clinical study.From November 28, 2019 to January 23, 2020, a total of 7904 outpatient children with signs of respiratory tract infection were admitted, and a total of 10102 throat swabs were collected. All the detection were performed to the throat swabs of patients, which include the epidemic statues, detection rate, duration of Flu A and B persistence in airway, and the positive rate of COVID-19 nucleic acid. Results: : A total of 10102 throat swabs were obtained from children with respiratory symptoms, including 5450 (53.9%) male and 4652 (46.1%) female. 2899 (28.7%) cases were positive for Influenza A. There were 617 (6.1% ) cases of Influenza B . In group of Influenza A , the lowest positive rate was in the infants less than 1 year old (18.4%), and the highest in the group 12 year old (32.1%). During the period of high prevalence of influenza A, there was a low level of infection of influenza B. The detection rate of each age group fluctuated from 3% to 10%. 73.7% of children's influenza A and B virus turned negative within 7 days, and very few children's respiratory influenza virus can last even more than 1 month. Among 35 throat swabs detected with qRT-PCR, 11 (31.4%) were positive for Flu A, and all children were negative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Conclusions: : In the early stage of SARS-CoV-2 transmission, children in Wuhan were experiencing a high intensity of influenza A pandemic, and there was no the mixed infection of SARS-CoV-2 with influenza A. COVID-19 spread caught up the tail of influenza A pandemic.

9.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-315356

ABSTRACT

Backgrounds: : COVID-19 is currently spreading around the world, and the cumulative number of cases worldwide exceeded 5 million on 23 May 2020 (10:00 GMT+2). At present, many countries or cities have implemented lockdown measures. This study evaluated the inhibitory effect of lockdown measures on the pandemic by the use of lockdown or similar lockdown in 22 countries or cities. Methods: : An SEIQR epidemiological model was developed to capture the transmission dynamics of COVID-19. With the data related to COVID-19 from 22 countries or cities, the optimal parameters of the model were estimated, respectively. Results: : The average basic reproduction numbers of 22 countries or cities were between 1.5286-3.8067. And Russia Federation, Spain, Italy, France, Germany, the United Kingdom, Singapore, the United States of New York and the United States of New Jersey were hardest hit by COVID-19. Conclusion: Although the pandemic has not been fundamentally controlled for a short time after lockdown, lockdown was proved to be an extremely effective control measure, which significantly scaled the number of patients down, thereby reduced the harmfulness of the pandemic.

10.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-315176

ABSTRACT

Background: Public perception of the disposal of discarded face masks during the Coronavirus Disease 2019 (COVID-19) pandemic remains unknown. Therefore, this study aimed to assess the cognition level and attitude of the public towards the disposal of discarded face masks during the COVID-19 pandemic, to provide a reference for a standardized disposal of discarded face masks. Methods: : The convenience sampling method was applied to conduct a questionnaire survey, assessing personal general information, as well as the management status of, attitudes towards and cognition of the disposal of discarded face masks. Results: : A total of 910 valid questionnaires were collected. The results showed that 47% of individuals had a low level of relevant knowledge about the disposal of discarded face masks, but more than 95% showed a positive attitude towards the cooperation with it. In addition, the participants had limited understanding of related regulations, and expected that the relevant departments should increase publicity and training to propagate the related information. Conclusions: : This study demonstrated variations in public cognition level and attitude towards the disposal of discarded face masks during the COVID-19 pandemic. Therefore, relevant departments should further clarify the refuse classification of and management regulations for discarded face masks, increase publicity, guide the public to correctly dispose of discarded face masks and enforce supervision, to prevent viral spread and secondary environmental contamination incidents, and to ensure public health and ecological environment safety.

11.
Genome Res ; 32(2): 228-241, 2022 02.
Article in English | MEDLINE | ID: covidwho-1642462

ABSTRACT

The pathogenesis of COVID-19 is still elusive, which impedes disease progression prediction, differential diagnosis, and targeted therapy. Plasma cell-free RNAs (cfRNAs) carry unique information from human tissue and thus could point to resourceful solutions for pathogenesis and host-pathogen interactions. Here, we performed a comparative analysis of cfRNA profiles between COVID-19 patients and healthy donors using serial plasma. Analyses of the cfRNA landscape, potential gene regulatory mechanisms, dynamic changes in tRNA pools upon infection, and microbial communities were performed. A total of 380 cfRNA molecules were up-regulated in all COVID-19 patients, of which seven could serve as potential biomarkers (AUC > 0.85) with great sensitivity and specificity. Antiviral (NFKB1A, IFITM3, and IFI27) and neutrophil activation (S100A8, CD68, and CD63)-related genes exhibited decreased expression levels during treatment in COVID-19 patients, which is in accordance with the dynamically enhanced inflammatory response in COVID-19 patients. Noncoding RNAs, including some microRNAs (let 7 family) and long noncoding RNAs (GJA9-MYCBP) targeting interleukin (IL6/IL6R), were differentially expressed between COVID-19 patients and healthy donors, which accounts for the potential core mechanism of cytokine storm syndromes; the tRNA pools change significantly between the COVID-19 and healthy group, leading to the accumulation of SARS-CoV-2 biased codons, which facilitate SARS-CoV-2 replication. Finally, several pneumonia-related microorganisms were detected in the plasma of COVID-19 patients, raising the possibility of simultaneously monitoring immune response regulation and microbial communities using cfRNA analysis. This study fills the knowledge gap in the plasma cfRNA landscape of COVID-19 patients and offers insight into the potential mechanisms of cfRNAs to explain COVID-19 pathogenesis.


Subject(s)
COVID-19 , Cell-Free Nucleic Acids , RNA/blood , COVID-19/blood , COVID-19/genetics , Cell-Free Nucleic Acids/blood , Cytokine Release Syndrome , Humans , SARS-CoV-2
12.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-294073

ABSTRACT

Successful control of the COVID-19 pandemic depends on vaccines that prevent transmission. The full-length Spike protein is highly immunogenic but the majority of antibodies do not target the virus: ACE2 interface. In an effort to concentrate the antibody response to the receptor-binding motif (RBM) we generated a series of conformationally-constrained immunogens by inserting solvent-exposed RBM amino acid residues into hypervariable loops of an immunoglobulin molecule. Priming C57BL/6 mice with plasmid (p)DNA encoding these constructs yielded a rapid memory response to booster immunization with recombinant Spike protein. Immune sera antibodies bound strongly to the purified receptor-binding domain (RBD) and Spike proteins. pDNA primed for a consistent response with antibodies efficient at neutralizing authentic WA1 virus and two variants of concern (VOC), B.1.351 and B.1.617.2. These findings demonstrate that immunogens built on structure selection can focus the response to conserved sites of vulnerability shared between wildtype virus and VOCs and induce neutralizing antibodies across variants.

13.
AAPS Open ; 7(1): 6, 2021.
Article in English | MEDLINE | ID: covidwho-1553521

ABSTRACT

The Stability Community of the American Association of Pharmaceutical Scientists (AAPS) held a virtual workshop on "Vaccine Stability Considerations to Enable Rapid Development and Deployment", on March 24-25, 2021. The workshop included distinguished speakers and panelists from across the industry, academia, regulatory agencies, as well as health care leaders. This paper presents a review of the topics covered. Specifically the challenges in accelerating vaccine development and analytical characterization techniques to establish shelf-life were covered. Additionally, vaccine stability modeling using prior knowledge stability models and advanced kinetic analysis played a key in the EUA approaches discussed during the workshop. Finally, the role of stability studies in addressing the challenges of vaccine distribution and deployment during the pandemic were a focus of presentations and panel discussions. Although the workshop did not have any presentation topics directly dedicated to the mRNA vaccines, the techniques discussed are generally applicable. The mRNA vaccine developers were represented in the panel discussions, where experts involved in the EUA approval/deployment stages for this vaccine type could discuss the challenges as applied to their vaccines.

14.
Int J Med Sci ; 18(13): 2849-2870, 2021.
Article in English | MEDLINE | ID: covidwho-1524511

ABSTRACT

Lung disorders are a leading cause of morbidity and death worldwide. For many disease conditions, no effective and curative treatment options are available. Mesenchymal stromal cell (MSC)-based therapy is one of the cutting-edge topics in medical research today. It offers a novel and promising therapeutic option for various acute and chronic lung diseases due to its potent and broad-ranging immunomodulatory activities, bacterial clearance, tissue regeneration, and proangiogenic and antifibrotic properties, which rely on both cell-to-cell contact and paracrine mechanisms. This review covers the sources and therapeutic potential of MSCs. In particular, a total of 110 MSC-based clinical applications, either completed clinical trials with safety and early efficacy results reported or ongoing worldwide clinical trials of pulmonary diseases, are systematically summarized following preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines, including acute/viral pulmonary disease, community-acquired pneumonia (CAP), chronic obstructive pulmonary disease (COPD), bronchopulmonary dysplasia (BPD), interstitial lung diseases (ILD), chronic pulmonary fibrosis, bronchiolitis obliterans syndrome (BOS) and lung cancer. The results of recent clinical studies suggest that MSCs are a promising therapeutic approach for the treatment of lung diseases. Nevertheless, large-scale clinical trials and evaluation of long-term effects are necessary in further studies.


Subject(s)
Lung Diseases/therapy , Mesenchymal Stem Cell Transplantation/statistics & numerical data , Clinical Trials as Topic , Humans , Mesenchymal Stem Cell Transplantation/adverse effects , Mesenchymal Stem Cell Transplantation/trends , Treatment Outcome
15.
Front Med (Lausanne) ; 8: 705943, 2021.
Article in English | MEDLINE | ID: covidwho-1468348

ABSTRACT

Purpose: To estimate whether the city-specific lockdown in Shanghai induced by the COVID-19 pandemic affected preterm birth rates among uninfected pregnant women in different trimesters. Methods: The population-based retrospective cohort study was conducted in the International Peace Maternity and Child Health Hospital (IPMCH) in Shanghai, China. Pregnant women without COVID-19 received perinatal healthcare during lockdown (from January 24, 2020 to March 24, 2020) and non-lockdown (from January 24, 2019 to March 24, 2019) period and giving birth to a live infant at IPMCH were enrolled. 1:1 propensity score matching and Inverse probability of treatment weighting were used to evaluate preterm birth (<37 weeks), very preterm birth (<34 weeks), preterm birth with premature rupture of membranes (PROM-PTB), spontaneous preterm birth with intact membranes (S-PTB), and medically induced preterm birth (MI-PTB) between two groups. Results: 8,270 pregnant women were in the lockdown group, and 9,815 were in the non-lockdown group. Pregnant women in second trimester during lockdown had a higher risk of PTB than those during the non-lockdown period [OR: 1.43 (CI 1.01-2.02), ARD: 1.7% (CI 0.04-3.4%), p = 0.045]. Furthermore, pregnant women in third trimester during lockdown had a higher risk of PROM-PTB than those during the non-lockdown period [OR: 1.64 (CI 1.09-2.47), ARD: 0.9% (CI 0.2-1.6%), p = 0.02]; no group differences were found related to rates of VPTB, S-PTB or MI-PTB. Conclusion: In this cohort study in China, we found that there was an increased risk in preterm birth for non-infected women in COVID-19 lockdown who were in their second trimester.

16.
Cell Discov ; 7(1): 82, 2021 Sep 07.
Article in English | MEDLINE | ID: covidwho-1397862

ABSTRACT

The pandemic of COVID-19 caused by SARS-CoV-2 has raised a new challenges to the scientific and industrious fields after over 1-year spread across different countries. The ultimate approach to end the pandemic is the timely application of vaccines to achieve herd immunity. Here, a novel SARS-CoV-2 receptor-binding domain (RBD) homodimer was developed as a SARS-CoV-2 vaccine candidate. Formulated with aluminum adjuvant, RBD dimer elicited strong immune response in both rodents and non-human primates, and protected mice from SARS-CoV-2 challenge with significantly reducing viral load and alleviating pathological injury in the lung. In the non-human primates, the vaccine could prevent majority of the animals from SARS-CoV-2 infection in the respiratory tract and reduce lung damage. In addition, antibodies elicited by this vaccine candidate showed cross-neutralization activities to SARS-CoV-2 variants. Furthermore, with our expression system, we provided a high-yield RBD homodimer vaccine without additional biosafety or special transport device supports. Thus, it may serve as a safe, effective, and low-cost SARS-CoV-2 vaccine candidate.

17.
Cell Res ; 31(8): 847-860, 2021 08.
Article in English | MEDLINE | ID: covidwho-1387284

ABSTRACT

Cytokine storm and multi-organ failure are the main causes of SARS-CoV-2-related death. However, the origin of excessive damages caused by SARS-CoV-2 remains largely unknown. Here we show that the SARS-CoV-2 envelope (2-E) protein alone is able to cause acute respiratory distress syndrome (ARDS)-like damages in vitro and in vivo. 2-E proteins were found to form a type of pH-sensitive cation channels in bilayer lipid membranes. As observed in SARS-CoV-2-infected cells, heterologous expression of 2-E channels induced rapid cell death in various susceptible cell types and robust secretion of cytokines and chemokines in macrophages. Intravenous administration of purified 2-E protein into mice caused ARDS-like pathological damages in lung and spleen. A dominant negative mutation lowering 2-E channel activity attenuated cell death and SARS-CoV-2 production. Newly identified channel inhibitors exhibited potent anti-SARS-CoV-2 activity and excellent cell protective activity in vitro and these activities were positively correlated with inhibition of 2-E channel. Importantly, prophylactic and therapeutic administration of the channel inhibitor effectively reduced both the viral load and secretion of inflammation cytokines in lungs of SARS-CoV-2-infected transgenic mice expressing human angiotensin-converting enzyme 2 (hACE-2). Our study supports that 2-E is a promising drug target against SARS-CoV-2.


Subject(s)
Antiviral Agents/metabolism , COVID-19/pathology , Coronavirus Envelope Proteins/metabolism , Respiratory Distress Syndrome/etiology , SARS-CoV-2/metabolism , Angiotensin-Converting Enzyme 2/genetics , Animals , Antiviral Agents/chemistry , Antiviral Agents/therapeutic use , Apoptosis , COVID-19/complications , COVID-19/drug therapy , COVID-19/virology , Coronavirus Envelope Proteins/antagonists & inhibitors , Coronavirus Envelope Proteins/genetics , Cytokines/metabolism , Disease Models, Animal , Half-Life , Humans , Lung/metabolism , Lung/pathology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Mutagenesis, Site-Directed , SARS-CoV-2/isolation & purification , SARS-CoV-2/pathogenicity , Spleen/metabolism , Spleen/pathology , Viral Load , Virulence
18.
Acta Pharmacol Sin ; 43(4): 781-787, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1387237

ABSTRACT

Lack of efficiency has been a major problem shared by all currently developed anti-SARS-CoV-2 therapies. Our previous study shows that SARS-CoV-2 structural envelope (2-E) protein forms a type of cation channel, and heterogeneously expression of 2-E channels causes host cell death. In this study we developed a cell-based high throughput screening (HTS) assay and used it to discover inhibitors against 2-E channels. Among 4376 compounds tested, 34 hits with cell protection activity were found. Followed by an anti-viral analysis, 15 compounds which could inhibit SARS-CoV-2 replication were identified. In electrophysiological experiments, three representatives showing inhibitory effect on 2-E channels were chosen for further characterization. Among them, proanthocyanidins directly bound to 2-E channel with binding affinity (KD) of 22.14 µM in surface plasmon resonance assay. Molecular modeling and docking analysis revealed that proanthocyanidins inserted into the pore of 2-E N-terminal vestibule acting as a channel blocker. Consistently, mutations of Glu 8 and Asn 15, two residues lining the proposed binding pocket, abolished the inhibitory effects of proanthocyanidins. The natural product proanthocyanidins are widely used as cosmetic, suggesting a potential of proanthocyanidins as disinfectant for external use. This study further demonstrates that 2-E channel is an effective antiviral drug target and provides a potential antiviral candidate against SARS-CoV-2.


Subject(s)
Antiviral Agents , COVID-19 , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , High-Throughput Screening Assays , Humans , Molecular Docking Simulation , SARS-CoV-2
19.
Psychol Health Med ; : 1-7, 2021 Aug 11.
Article in English | MEDLINE | ID: covidwho-1352042

ABSTRACT

The coronavirus pneumonia 2019 epidemic has had a huge impact on the population, and medical students are no exception. The purpose of this study was to explore the correlation between the risk perception, adaptation, confidence, and risk response behavior of medical postgraduates. A cross-sectional survey on medical postgraduates was conducted in a medical school in China. A total of 712 students were investigated. Basic information and individual scores, including risk perception, adaptability, confidence, and risk response behavior, were collected. There was a significant positive correlation between risk perception and adaptability, confidence, and risk response behavior (P < 0.01). Not only did risk perception have a direct positive predictive effect on adaptability, but also affected adaptability through three indirect pathways.

20.
Acta Pharmacol Sin ; 43(4): 788-796, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1343437

ABSTRACT

An epidemic of pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is spreading worldwide. SARS-CoV-2 relies on its spike protein to invade host cells by interacting with the human receptor protein Angiotensin-Converting Enzymes 2 (ACE2). Therefore, designing an antibody or small-molecular entry blockers is of great significance for virus prevention and treatment. This study identified five potential small molecular anti-virus blockers via targeting SARS-CoV-2 spike protein by combining in silico technologies with in vitro experimental methods. The five molecules were natural products that binding to the RBD domain of SARS-CoV-2 was qualitatively and quantitively validated by both native Mass Spectrometry (MS) and Surface Plasmon Resonance (SPR). Anti-viral activity assays showed that the optimal molecule, H69C2, had a strong binding affinity (dissociation constant KD) of 0.0947 µM and anti-virus IC50 of 85.75 µM.


Subject(s)
COVID-19 , Spike Glycoprotein, Coronavirus , COVID-19/drug therapy , Humans , Protein Binding , SARS-CoV-2
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