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1.
iScience ; 25(4), 2022.
Article in English | EuropePMC | ID: covidwho-1781054

ABSTRACT

Summary Broadly effective antiviral therapies must be developed to be ready for clinical trials, which should begin soon after the emergence of new life-threatening viruses. Here, we pave the way towards this goal by reviewing conserved druggable virus-host interactions, mechanisms of action, immunomodulatory properties of available broad-spectrum antivirals (BSAs), routes of BSA delivery, and interactions of BSAs with other antivirals. Based on the review, we concluded that the range of indications of BSAs can be expanded, and new pan- and cross-viral mono- and combinational therapies can be developed. We have also developed a new scoring algorithm that can help identify the most promising few of the thousands of potential BSAs and BSA-containing drug cocktails (BCCs) to prioritize their development during the critical period between the identification of a new virus and the development of virus-specific vaccines, drugs, and therapeutic antibodies. Graphical Pharmaceutical preparation;Pharmaceutical science;Pharmacology;Chemistry

2.
Future Med Chem ; 14(10): 685-699, 2022 May.
Article in English | MEDLINE | ID: covidwho-1780171

ABSTRACT

Background: In the last two decades, the world has witnessed the emergence of zoonotic corona viruses (CoVs), which cause mild to severe respiratory diseases in humans. Human coronaviruses (HCoVs), mainly from the alpha-CoV and beta-CoV genera, have evolved to be highly pathogenic, such as SARS-CoV-2 causing the COVID-19 pandemic. These coronaviruses carry functional enzymes necessary for the virus life cycle, which represent attractive antiviral targets. Methods & Results: We aimed to therapeutically target the main protease (Mpro) of HCoV-NL63 and HCoV-229E (from alpha-CoV genus) and HCoV-OC43 and SARS-CoV-2 (from beta-CoV genus). Through virtual screening, we identified an FDA-approved drug dyphylline, a xanthine derivate, that binds to the catalytic dyad residues; histidine and cystine of the Mpro structures. Importantly, dyphylline dose-dependently inhibited the viral replication in cell culture models infected with the viruses. Conclusion: Our findings support the repurposing of dyphylline as a pan-coronavirus antiviral agent.


Subject(s)
COVID-19 , Dyphylline , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , COVID-19/drug therapy , Drug Repositioning , Humans , Pandemics , SARS-CoV-2
4.
Arch Virol ; 167(4): 1125-1130, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1694546

ABSTRACT

Given the structural similarities of the viral enzymes of different coronaviruses (CoVs), we investigated the potency of the anti-SARS-CoV-2 agents boceprevir and GC376 for counteracting seasonal coronavirus infections. In contrast to previous findings that both boceprevir and GC376 are potent inhibitors of the main protease (Mpro) of SARS-CoV-2, we found that GC376 is much more effective than boceprevir in inhibiting SARS-CoV-2 and three seasonal CoVs (NL63, 229E, and OC43) in cell culture models. However, these results are discordant with a molecular docking analysis that suggested comparable affinity of boceprevir and GC376 for the different Mpro enzymes of the four CoVs. Collectively, our results support future development of GC376 but not boceprevir (although it is an FDA-approved antiviral medication) as a pan-coronavirus antiviral agent. Furthermore, we caution against overinterpretation of in silico data when developing antiviral therapies.


Subject(s)
Antiviral Agents , COVID-19 , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , COVID-19/drug therapy , Humans , Molecular Docking Simulation , Proline/analogs & derivatives , Protease Inhibitors/pharmacology , Pyrrolidines , SARS-CoV-2 , Sulfonic Acids
6.
Int J Pept Res Ther ; 28(1): 28, 2022.
Article in English | MEDLINE | ID: covidwho-1568383

ABSTRACT

Several mutations in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have increased the transmission and mortality rate of coronavirus disease-19 (COVID-19) across the globe. Although many vaccines have been developed, a large proportion of the global population remains at high risk of infection. The current study aims to develop an antiviral peptide capable of inhibiting the interaction of SARS-CoV-2 spike protein and its six major variants with the host cell angiotensin-converting enzyme 2 (ACE2) receptor. An in-silico approach was employed to design a therapeutic peptide inhibitor against the receptor-binding domain (RBD) of the spike (S) protein of SARS-CoV-2 and its variants (B.1.1.7, B.1.351, P.1, B.1.617.1, B.1.617.2 and B.1.617.3). The binding specificity and affinity of our designed peptide inhibitor Mod13AApi (YADKYQKQYKDAY) with wild-type S-RBD and its six variants was confirmed by molecular docking using the HPEPDOCK tool, whereas complex stability was determined by the MD simulation study. The physicochemical and ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties of inhibitory peptides were determined using the ExPASy tool and pkCSM server. The docking results and its properties from our in-silico analysis present the Mod13AApi, a promising peptide for the rapid development of anti-coronavirus peptide-based antiviral therapy. Blockage of the binding of the spike protein of SARS-CoV-2 variants with ACE2 in the presence of the therapeutic peptide may prevent deadly SARS-CoV-2 variants entry into host cells. Therefore, the designed inhibitory peptide can be utilized as a promising therapeutic strategy to combat COVID-19, as evident from this in-silico study.

7.
Sci Rep ; 11(1): 23465, 2021 12 06.
Article in English | MEDLINE | ID: covidwho-1556248

ABSTRACT

Human coronavirus NL63 (HCoV-NL63) mainly affects young children and immunocompromised patients, causing morbidity and mortality in a subset of patients. Since no specific treatment is available, this study aims to explore the anti-SARS-CoV-2 agents including favipiravir and remdesivir for treating HCoV-NL63 infection. We first successfully modelled the 3D structure of HCoV-NL63 RNA-dependent RNA polymerase (RdRp) based on the experimentally solved SARS-CoV-2 RdRp structure. Molecular docking indicated that favipiravir has similar binding affinities to SARS-CoV-2 and HCoV-NL63 RdRp with LibDock scores of 75 and 74, respectively. The LibDock scores of remdesivir to SARS-CoV-2 and HCoV-NL63 were 135 and 151, suggesting that remdesivir may have a higher affinity to HCoV-NL63 compared to SARS-CoV-2 RdRp. In cell culture models infected with HCoV-NL63, both favipiravir and remdesivir significantly inhibited viral replication and production of infectious viruses. Overall, remdesivir compared to favipiravir is more potent in inhibiting HCoV-NL63 in cell culture. Importantly, there is no evidence of resistance development upon long-term exposure to remdesivir. Furthermore, combining favipiravir or remdesivir with the clinically used antiviral cytokine interferon-alpha resulted in synergistic effects. These findings provided a proof-of-concept that anti-SARS-CoV-2 drugs, in particular remdesivir, have the potential to be repurposed for treating HCoV-NL63 infection.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Amides/chemistry , Antiviral Agents/chemistry , Coronavirus NL63, Human/enzymology , Pyrazines/chemistry , RNA-Dependent RNA Polymerase/chemistry , Adenosine Monophosphate/chemistry , Adenosine Monophosphate/metabolism , Adenosine Monophosphate/pharmacology , Alanine/chemistry , Alanine/metabolism , Alanine/pharmacology , Amides/metabolism , Amides/pharmacology , Animals , Antiviral Agents/metabolism , Antiviral Agents/pharmacology , Binding Sites , Cell Culture Techniques , Cell Line , Coronavirus NL63, Human/physiology , Haplorhini , Humans , Molecular Docking Simulation , Pyrazines/metabolism , Pyrazines/pharmacology , RNA-Dependent RNA Polymerase/metabolism , Virus Replication/drug effects
8.
Virology ; 564: 33-38, 2021 12.
Article in English | MEDLINE | ID: covidwho-1447220

ABSTRACT

Endemic seasonal coronaviruses cause morbidity and mortality in a subset of patients, but no specific treatment is available. Molnupiravir is a promising pipeline antiviral drug for treating SARS-CoV-2 infection potentially by targeting RNA-dependent RNA polymerase (RdRp). This study aims to evaluate the potential of repurposing molnupiravir for treating seasonal human coronavirus (HCoV) infections. Molecular docking revealed that the active form of molnupiravir, ß-D-N4-hydroxycytidine (NHC), has similar binding affinity to RdRp of SARS-CoV-2 and seasonal HCoV-NL63, HCoV-OC43 and HCoV-229E. In cell culture models, treatment of molnupiravir effectively inhibited viral replication and production of infectious viruses of the three seasonal coronaviruses. A time-of-drug-addition experiment indicates the specificity of molnupiravir in inhibiting viral components. Furthermore, combining molnupiravir with the protease inhibitor GC376 resulted in enhanced antiviral activity. Our findings highlight that the great potential of repurposing molnupiravir for treating seasonal coronavirus infected patients.


Subject(s)
Coronavirus 229E, Human/genetics , Coronavirus Infections/drug therapy , Coronavirus NL63, Human/genetics , Coronavirus OC43, Human/genetics , Cytidine/analogs & derivatives , Hydroxylamines/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Antiviral Agents/pharmacology , Common Cold/drug therapy , Coronavirus 229E, Human/drug effects , Coronavirus 229E, Human/physiology , Coronavirus NL63, Human/drug effects , Coronavirus NL63, Human/physiology , Coronavirus OC43, Human/drug effects , Coronavirus OC43, Human/physiology , Cytidine/pharmacology , Humans , Molecular Docking Simulation , Protein Binding/drug effects , Pyrrolidines/pharmacology , RNA-Dependent RNA Polymerase/chemistry , RNA-Dependent RNA Polymerase/genetics , RNA-Dependent RNA Polymerase/metabolism , Seasons , Sulfonic Acids/pharmacology , Virus Replication/drug effects , Virus Replication/genetics
9.
Transbound Emerg Dis ; 2021 May 09.
Article in English | MEDLINE | ID: covidwho-1388406

ABSTRACT

Highly pathogenic coronaviruses, including SARS-CoV-2, SARS-CoV and MERS-CoV, are thought to be transmitted from bats to humans, but the viral genetic signatures that contribute to bat-to-human transmission remain largely obscure. In this study, we identified an identical ribosomal frameshift motif among the three bat-human pairs of viruses and strong purifying selection after jumping from bats to humans. This represents genetic signatures of coronaviruses that are related to bat-to-human transmission. To further trace the early human-to-human transmission of SARS-CoV-2 in North America, a geographically stratified genome-wide association study (North American isolates and the remaining isolates) and a retrospective study were conducted. We determined that the single nucleotide polymorphisms (SNPs) 1,059.C > T and 25,563.G > T were significantly associated with approximately half of the North American SARS-CoV-2 isolates that accumulated largely during March 2020. Retrospectively tracing isolates with these two SNPs was used to reconstruct the early, reliable transmission history of North American SARS-CoV-2, and European isolates (February 26, 2020) showed transmission 3 days earlier than North American isolates and 17 days earlier than Asian isolates. Collectively, we identified the genetic signatures of the three pairs of coronaviruses and reconstructed an early transmission history of North American SARS-CoV-2. We envision that these genetic signatures are possibly diagnosable and predic markers for public health surveillance.

11.
Drugs R D ; 21(3): 273-283, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1330440

ABSTRACT

BACKGROUND AND OBJECTIVE: Coronavirus disease 2019 is a novel disease caused by the severe acute respiratory syndrome coronavirus (SARS-CoV)-2 virus. It was first detected in December 2019 and has since been declared a pandemic causing millions of deaths worldwide. Therefore, there is an urgent need to develop effective therapeutics against coronavirus disease 2019. A critical step in the crosstalk between the virus and the host cell is the binding of the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein to the peptidase domain of the angiotensin-converting enzyme 2 (ACE2) receptor present on the surface of host cells. METHODS: An in silico approach was employed to design a 13-amino acid peptide inhibitor (13AApi) against the RBD of the SARS-CoV-2 spike protein. Its binding specificity for RBD was confirmed by molecular docking using pyDockWEB, ClusPro 2.0, and HDOCK web servers. The stability of 13AApi and the SARS-CoV-2 spike protein complex was determined by molecular dynamics simulation using the GROMACS program while the physicochemical and ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties of 13AApi were determined using the ExPASy tool and pkCSM server. Finally, in vitro validation of the inhibitory activity of 13AApi against the spike protein was performed by an enzyme-linked immunosorbent assay. RESULTS: In silico analyses indicated that the 13AApi could bind to the RBD of the SARS-CoV-2 spike protein at the ACE2 binding site with high affinity. In vitro experiments validated the in silico findings, showing that 13AApi could significantly block the RBD of the SARS-CoV-2 spike protein. CONCLUSIONS: Blockage of binding of the SARS-CoV-2 spike protein with ACE2 in the presence of the 13AApi may prevent virus entry into host cells. Therefore, the 13AApi can be utilized as a promising therapeutic agent to combat coronavirus disease 2019.


Subject(s)
Angiotensin-Converting Enzyme 2/drug effects , Antiviral Agents/pharmacology , Peptides/pharmacology , Spike Glycoprotein, Coronavirus/drug effects , Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/pharmacokinetics , Antiviral Agents/toxicity , Binding Sites , Computer Simulation , Drug Design , Humans , Models, Molecular , Molecular Docking Simulation , Molecular Dynamics Simulation , Molecular Structure , Peptides/pharmacokinetics , Peptides/toxicity , Protein Binding/drug effects , Spike Glycoprotein, Coronavirus/metabolism , Substrate Specificity
12.
World J Psychiatry ; 11(6): 232-241, 2021 Jun 19.
Article in English | MEDLINE | ID: covidwho-1282701

ABSTRACT

BACKGROUND: The ongoing coronavirus disease 2019 (COVID-19) pandemic and the universal implementation of control measures are fundamentally affecting every aspect of our society and daily lives. AIM: To evaluate the prevalence of post-traumatic stress disorder symptoms and their associated factors as well as the effects and attitudes towards online education in Chinese high school students. METHODS: A total of 883 students were included. The first, second and third-year students of a high school in Lanzhou, Gansu province of China were invited to participate in this study. They were requested to involve their parents to complete the survey together. A detailed questionnaire of 65 questions was designed and divided into five sections. The survey was anonymously conducted via WeChat, a Chinese multipurpose messaging, social media and mobile payment app. RESULTS: Overall, 32.94% of students experienced post-traumatic stress disorder due to the COVID-19 epidemic. The majority of students (60.82%) felt that online education was not (10.76%) or less effective (50.06%) in terms of gaining knowledge and improving practical and communications skills. Correlation analysis revealed that the class level, residential background and whether living with parents were significantly linked with the effectiveness and satisfaction of the online education system. Of the final year students, 74.2% said that the COVID-19 outbreak has negatively affected their preparation for the college entrance exam, and 68% of students felt that this outbreak increased psychological pressure for their college entrance examination preparation. In case of having COVID-19 symptoms during the exam, 50.7%, 13.3%, and 10.2% would notify the proctor, teacher and parents, respectively. CONCLUSION: We found a high prevalence rate of post-traumatic stress disorder symptoms in high school students. Thus, our results call for urgent attention from both government and schools to implement effective interventions to cope with the psychological effects and the disturbance of education by COVID-19 on children.

13.
World J Psychiatry ; 11(5): 181-200, 2021 May 19.
Article in English | MEDLINE | ID: covidwho-1248352

ABSTRACT

BACKGROUND: Measures for effective control of the coronavirus disease 2019 (COVID-19) pandemic include identifying the causal organisms, applying appropriate therapies, and developing vaccines, as well as improving understanding among the general public. AIM: To evaluate the knowledge, awareness, perception, and response of the general public to COVID-19 in China. METHODS: A detailed questionnaire comprising 47 questions designed in both English and Chinese was developed. The survey was conducted via WeChat, a multipurpose messaging, social media, and mobile payment app that is widely used by the Chinese population. In total, 1006 participants responded, and most of them were from different provinces of mainland China. RESULTS: Overall, this comprehensive survey revealed that the general public in China is highly aware of the basic information concerning COVID-19 and its precautions. Interestingly, more respondents (99.3%) were aware of the term severe acute respiratory syndrome (SARS) than COVID-19 (97.2%) and Middle East respiratory syndrome (MERS) (73.4%). Among them, 2.4%, 1.6%, and 0.9% said that they or their family members or friends were affected by COVID-19, SARS, and MERS, respectively. The majority of the respondents (91.2%) indicated that knowledge about COVID-19 was received mainly from WeChat, followed by TV (89%), friends (76.1%), and QQ (a Chinese instant messaging software service) (57.7%). CONCLUSION: The general public in China is highly aware of COVID-19 and the necessary precautions. Unexpectedly, 2.8% of the participants were unaware of the current epidemic. The remaining information gaps highlight the necessity of further enhancing awareness and preparedness.

14.
BMC Pediatr ; 21(1): 95, 2021 02 24.
Article in English | MEDLINE | ID: covidwho-1102333

ABSTRACT

BACKGROUND: The emerging of psychological problems triggered by COVID-19 particularly in children have been extensively highlighted and emphasized, but original research in this respect is still lagging behind. Therefore, we designed this study to evaluate the impact of COVID-19 pandemic on mental health and the effectiveness and attitudes towards online education among Chinese children aged 7-15 years. METHODS: A detailed questionnaire, comprising of 62 questions was designed and parents or caretakers of 7 to 15 years old children were invited to participate via WeChat, a multi-purpose messaging, social media and mobile payment app, which is widely used by the Chinese population. A total of 668 parents across different regions of China were included. RESULTS: During COVID-19 pandemic, 20.7 and 7.2% children report experiencing post-traumatic stress disorder (PTSD) and depressive symptoms due to the COVID-19 pandemic. PTSD and SMFQ-P scores are significantly higher in middle school and boarding school students compared to primary and day school students. Multiple logistic regression analysis revealed that school system and province of origin are factors significantly associated with developing PSTD symptoms. 44.3% respondents feel online education is effective in gaining knowledge and improving practical and communications skills. 78.0% believe the online education system is efficient. Overall 79.8% respondents are satisfied and children can adapt to this new education system. During the COVID-19 pandemic, we found 1 in five children have PTSD and 1 in 14 children have depressive symptoms. CONCLUSION: In summary, COVID-19 epidemic has caused PTSD and depression symptoms among Chinese children aged 7 to 15 years. In general, a large proportion of respondents are satisfied with online education, but still a substantial proportion of students are not comfortable with this new form of learning. Authorities should optimize online education systems and implement effective interventions to cope with the psychological effects of COVID-19 on children, as it is affecting the global population and remains uncertain when it will end.


Subject(s)
COVID-19/psychology , Depression/epidemiology , Mental Health , Pandemics , Stress Disorders, Post-Traumatic/epidemiology , Adolescent , Child , China/epidemiology , Cross-Sectional Studies , Humans , Surveys and Questionnaires
15.
Transbound Emerg Dis ; 69(2): 549-558, 2022 Mar.
Article in English | MEDLINE | ID: covidwho-1096940

ABSTRACT

Epicentres are the focus of COVID-19 research, whereas emerging regions with mainly imported cases due to population movement are often neglected. Classical compartmental models are useful, however, likely oversimplify the complexity when studying epidemics. This study aimed to develop a multi-regional, hierarchical-tier mathematical model for better understanding the complexity and heterogeneity of COVID-19 spread and control. By incorporating the epidemiological and population flow data, we have successfully constructed a multi-regional, hierarchical-tier SLIHR model. With this model, we revealed insight into how COVID-19 was spread from the epicentre Wuhan to other regions in Mainland China based on the large population flow network data. By comprehensive analysis of the effects of different control measures, we identified that Level 1 emergency response, community prevention and application of big data tools significantly correlate with the effectiveness of local epidemic containment across different provinces of China outside the epicentre. In conclusion, our multi-regional, hierarchical-tier SLIHR model revealed insight into how COVID-19 spread from the epicentre Wuhan to other regions of China, and the subsequent control of local epidemics. These findings bear important implications for many other countries and regions to better understand and respond to their local epidemics associated with the ongoing COVID-19 pandemic.


Subject(s)
COVID-19 , Epidemics , Animals , COVID-19/epidemiology , COVID-19/prevention & control , COVID-19/veterinary , China/epidemiology , Cities , Epidemics/prevention & control , Models, Theoretical , Pandemics/prevention & control
16.
J Epidemiol Community Health ; 2021 Feb 16.
Article in English | MEDLINE | ID: covidwho-1088280
17.
Int J Infect Dis ; 102: 375-380, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-1060138

ABSTRACT

OBJECTIVES: This study aimed to comprehensively compare the clinical features of hospitalized COVID-19 patients with hospitalized 2009 influenza pandemic patients. METHODS: Medline, Embase, Web of Science, Cochrane CENTRAL, and Google scholar were systematically searched to identify studies related to COVID-19 and the 2009 influenza pandemic. The pooled incidence rates of clinical features were estimated using the DerSimonian-Laird random-effects model with the Freeman-Tukey double arcsine transformation method. RESULTS: The incidence rates of fever, cough, shortness of breath, sore throat, rhinorrhea, myalgia/muscle pain, or vomiting were found to be significantly higher in influenza patients when compared with COVID-19 patients. The incidence rates of comorbidities, including cardiovascular disease/hypertension and diabetes, were significantly higher in COVID-19 compared with influenza patients. In contrast, comorbidities such as asthma, chronic obstructive pulmonary disease, and immunocompromised conditions were significantly more common in influenza compared with COVID-19 patients. Unexpectedly, the estimated rates of intensive care unit admission, treatment with extracorporeal membrane oxygenation, treatment with antibiotics, and fatality were comparable between hospitalized COVID-19 and 2009 influenza pandemic patients. CONCLUSIONS: This study comprehensively estimated the differences and similarities of the clinical features and burdens of hospitalized COVID-19 and 2009 influenza pandemic patients. This information will be important to better understand the current COVID-19 pandemic.


Subject(s)
COVID-19/therapy , Influenza, Human/therapy , Adolescent , Adult , Aged , Aged, 80 and over , COVID-19/diagnosis , COVID-19/epidemiology , COVID-19/virology , Child , Child, Preschool , Female , Hospitalization , Humans , Infant , Influenza, Human/diagnosis , Influenza, Human/epidemiology , Influenza, Human/virology , Male , Middle Aged , Orthomyxoviridae/physiology , Pandemics , SARS-CoV-2/physiology , Young Adult
18.
International Journal of Infectious Diseases ; 2020.
Article in English | ScienceDirect | ID: covidwho-919646

ABSTRACT

Objectives This study aims to comprehensively compare the clinical features of hospitalized COVID-19 patients with hospitalized 2009 influenza pandemic patients. Methods We systematically searched Medline, Embase, Web of science, Cochrane CENTRAL and Google scholar to identify studies related to COVID-19 and 2009 influenza pandemic. The pooled incidence rates of clinical features were estimated using DerSimonian-Laird random-effects model with Freeman-Tukey double arcsine transformation method. Results We found the incidence rates of fever, cough, shortness of breath, sore throat, rhinorrhea, myalgia/muscle pain or vomiting were significantly higher in influenza compared to COVID-19 patients. The incidence rates of comorbidities including cardiovascular disease/ hypertension and diabetes were significantly higher in COVID-19 patients compared with influenza patients. In contrast, comorbidities such as asthma, chronic obstructive pulmonary disease and immunocompromised conditions were significantly more common in influenza compared to COVID-19 patients. Unexpectedly, the estimated rates of intensive care unit admission, treatment with extracorporeal membrane oxygenation, treatment with antibiotics and fatality were comparable between hospitalized COVID-19 and 2009 influenza pandemic patients. Conclusions This study comprehensively estimated the differences and similarities of the clinical features and burdens of hospitalized COVID-19 and 2009 influenza pandemic patients. These knowledge will be important for better understanding the current COVID-19 pandemic.

19.
SSRN; 2020.
Preprint | SSRN | ID: ppcovidwho-1603

ABSTRACT

Background: An emerging theory suggests that pre-exposure to low pathogenic human coronaviruses (LPH-CoV) may cross-protect SARS-CoV-2 infection, the causative

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