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1.
Biosci Rep ; 41(10)2021 10 29.
Article in English | MEDLINE | ID: covidwho-1510636

ABSTRACT

Coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has become a global health emergency. Although new vaccines have been generated and being implicated, discovery and application of novel preventive and control measures are warranted. We aimed to identify compounds that may possess the potential to either block the entry of virus to host cells or attenuate its replication upon infection. Using host cell surface receptor expression (angiotensin-converting enzyme 2 (ACE2) and Transmembrane protease serine 2 (TMPRSS2)) analysis as an assay, we earlier screened several synthetic and natural compounds and identified candidates that showed ability to down-regulate their expression. Here, we report experimental and computational analyses of two small molecules, Mortaparib and MortaparibPlus that were initially identified as dual novel inhibitors of mortalin and PARP-1, for their activity against SARS-CoV-2. In silico analyses showed that MortaparibPlus, but not Mortaparib, stably binds into the catalytic pocket of TMPRSS2. In vitro analysis of control and treated cells revealed that MortaparibPlus caused down-regulation of ACE2 and TMPRSS2; Mortaparib did not show any effect. Furthermore, computational analysis on SARS-CoV-2 main protease (Mpro) that also predicted the inhibitory activity of MortaparibPlus. However, cell-based antiviral drug screening assay showed 30-60% viral inhibition in cells treated with non-toxic doses of either MortaparibPlus or Mortaparib. The data suggest that these two closely related compounds possess multimodal anti-COVID-19 activities. Whereas MortaparibPlus works through direct interactions/effects on the host cell surface receptors (ACE2 and TMPRSS2) and the virus protein (Mpro), Mortaparib involves independent mechanisms, elucidation of which warrants further studies.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Computational Biology/methods , Angiotensin-Converting Enzyme 2/immunology , Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/immunology , COVID-19/immunology , Cell Line, Tumor , Drug Evaluation, Preclinical/methods , HSP70 Heat-Shock Proteins/antagonists & inhibitors , Humans , Mitochondrial Proteins/antagonists & inhibitors , Poly (ADP-Ribose) Polymerase-1/antagonists & inhibitors , SARS-CoV-2/immunology , Serine Endopeptidases/immunology , Serine Endopeptidases/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Virus Internalization/drug effects
2.
Eur J Immunol ; 51(7): 1641-1651, 2021 07.
Article in English | MEDLINE | ID: covidwho-1473829

ABSTRACT

Emerging life-threatening viruses have posed great challenges to public health. It is now increasingly clear that epigenetics plays a role in shaping host-virus interactions and there is a great need for a more thorough understanding of these intricate interactions through the epigenetic lens, which may represent potential therapeutic opportunities in the clinic. In this review, we highlight the current understanding of the roles of key epigenetic regulators - chromatin remodeling and histone modification - in modulating chromatin openness during host defense against virus. We also discuss how the RNA modification m6A (N6-methyladenosine) affects fundamental aspects of host-virus interactions. We conclude with future directions for uncovering more detailed functions that epigenetic regulation exerts on both host cells and viruses during infection.


Subject(s)
Antiviral Agents/immunology , Epigenesis, Genetic/genetics , Epigenesis, Genetic/immunology , Immunity, Innate/genetics , Immunity, Innate/immunology , Animals , Chromatin/genetics , Chromatin/immunology , Histones/genetics , Histones/immunology , Host Microbial Interactions/genetics , Host Microbial Interactions/immunology , Humans , RNA Processing, Post-Transcriptional/genetics , RNA Processing, Post-Transcriptional/immunology
3.
Sci Rep ; 11(1): 20274, 2021 10 12.
Article in English | MEDLINE | ID: covidwho-1467137

ABSTRACT

The purpose of this work is to provide an in silico molecular rationale of the role eventually played by currently circulating mutations in the receptor binding domain of the SARS-CoV-2 spike protein (S-RBDCoV­2) in evading the immune surveillance effects elicited by the two Eli Lilly LY-CoV555/bamlanivimab and LY-CoV016/etesevimab monoclonal antibodies. The main findings from this study show that, compared to the wild-type SARS-CoV-2 spike protein, mutations E484A/G/K/Q/R/V, Q493K/L/R, S494A/P/R, L452R and F490S are predicted to be markedly resistant to neutralization by LY-CoV555, while mutations K417E/N/T, D420A/G/N, N460I/K/S/T, T415P, and Y489C/S are predicted to confer LY-CoV016 escaping advantage to the viral protein. A challenge of our global in silico results against relevant experimental data resulted in an overall 90% agreement. Thus, the results presented provide a molecular-based rationale for all relative experimental findings, constitute a fast and reliable tool for identifying and prioritizing all present and newly reported circulating spike SARS-CoV-2 variants with respect to antibody neutralization, and yield substantial structural information for the development of next-generation vaccines and monoclonal antibodies more resilient to viral evolution.


Subject(s)
Antibodies, Monoclonal, Humanized/immunology , Antiviral Agents/immunology , COVID-19/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Humans , Protein Binding
4.
Biomed Pharmacother ; 144: 112247, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1446461

ABSTRACT

COVID-19 is a pneumonia-like disease with highly transmittable and pathogenic properties caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which infects both animals and humans. Although many efforts are currently underway to test possible therapies, there is no specific FDA approved drug against SARS-CoV-2 yet. miRNA-directed gene regulation controls the majority of biological processes. In addition, the development and progression of several human diseases are associated with dysregulation of miRNAs. In this regard, it has been shown that changes in miRNAs are linked to severity of COVID-19 especially in patients with respiratory diseases, diabetes, heart failure or kidney problems. Therefore, targeting these small noncoding-RNAs could potentially alleviate complications from COVID-19. Here, we will review the roles and importance of host and RNA virus encoded miRNAs in COVID-19 pathogenicity and immune response. Then, we focus on potential miRNA therapeutics in the patients who are at increased risk for severe disease.


Subject(s)
Antiviral Agents/administration & dosage , COVID-19/therapy , Genetic Therapy/methods , MicroRNAs/administration & dosage , Animals , Antiviral Agents/immunology , COVID-19/genetics , COVID-19/immunology , Drug Delivery Systems/methods , Humans , MicroRNAs/genetics , MicroRNAs/immunology
5.
Signal Transduct Target Ther ; 6(1): 315, 2021 08 25.
Article in English | MEDLINE | ID: covidwho-1442755

ABSTRACT

The evolution of coronaviruses, such as SARS-CoV-2, makes broad-spectrum coronavirus preventional or therapeutical strategies highly sought after. Here we report a human angiotensin-converting enzyme 2 (ACE2)-targeting monoclonal antibody, 3E8, blocked the S1-subunits and pseudo-typed virus constructs from multiple coronaviruses including SARS-CoV-2, SARS-CoV-2 mutant variants (SARS-CoV-2-D614G, B.1.1.7, B.1.351, B.1.617.1, and P.1), SARS-CoV and HCoV-NL63, without markedly affecting the physiological activities of ACE2 or causing severe toxicity in ACE2 "knock-in" mice. 3E8 also blocked live SARS-CoV-2 infection in vitro and in a prophylactic mouse model of COVID-19. Cryo-EM and "alanine walk" studies revealed the key binding residues on ACE2 interacting with the CDR3 domain of 3E8 heavy chain. Although full evaluation of safety in non-human primates is necessary before clinical development of 3E8, we provided a potentially potent and "broad-spectrum" management strategy against all coronaviruses that utilize ACE2 as entry receptors and disclosed an anti-coronavirus epitope on human ACE2.


Subject(s)
Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Antibodies, Monoclonal, Murine-Derived/pharmacology , Antiviral Agents/pharmacology , COVID-19/drug therapy , SARS-CoV-2/immunology , Angiotensin-Converting Enzyme 2/immunology , Animals , Antibodies, Monoclonal, Murine-Derived/immunology , Antiviral Agents/immunology , Chlorocebus aethiops , Disease Models, Animal , HEK293 Cells , Humans , Mice , Mice, Inbred BALB C , Mice, Transgenic , Vero Cells
6.
Biomed Pharmacother ; 143: 112228, 2021 Nov.
Article in English | MEDLINE | ID: covidwho-1432983

ABSTRACT

Coronavirus disease 2019 (COVID-19), which is a respiratory illness associated with high mortality, has been classified as a pandemic. The major obstacles for the clinicians to contain the disease are limited information availability, difficulty in disease diagnosis, predicting disease prognosis, and lack of disease monitoring tools. Additionally, the lack of valid therapies has further contributed to the difficulties in containing the pandemic. Recent studies have reported that the dysregulation of the immune system leads to an ineffective antiviral response and promotes pathological immune response, which manifests as ARDS, myocarditis, and hepatitis. In this study, a novel platform has been described for disseminating information to physicians for the diagnosis and monitoring of patients with COVID-19. An adjuvant approach using compounds that can potentiate antiviral immune response and mitigate COVID-19-induced immune-mediated target organ damage has been presented. A prolonged beneficial effect is achieved by implementing algorithm-based individualized variability measures in the treatment regimen.


Subject(s)
Antiviral Agents/immunology , Antiviral Agents/therapeutic use , COVID-19/diagnosis , COVID-19/drug therapy , Chemotherapy, Adjuvant/methods , Medical Informatics/methods , Algorithms , COVID-19/immunology , Disease Management , Disease Progression , Gastrointestinal Tract/immunology , Humans , Immunity, Cellular , Immunity, Humoral , Severity of Illness Index
7.
Arch Immunol Ther Exp (Warsz) ; 69(1): 25, 2021 Sep 16.
Article in English | MEDLINE | ID: covidwho-1411512

ABSTRACT

The term host defense peptides arose at the beginning to refer to those peptides that are part of the host's immunity. Because of their broad antimicrobial capacity and immunomodulatory activity, nowadays, they emerge as a hope to combat resistant multi-drug microorganisms and emerging viruses, such as the case of coronaviruses. Since the beginning of this century, coronaviruses have been part of different outbreaks and a pandemic, and they will be surely part of the next pandemics, this review analyses whether these peptides and their derivatives are ready to be part of the treatment of the next coronavirus pandemic.


Subject(s)
Antimicrobial Cationic Peptides/therapeutic use , Antiviral Agents/therapeutic use , Coronavirus Infections/drug therapy , Coronavirus Infections/epidemiology , Pandemics , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/immunology , Anti-Inflammatory Agents/therapeutic use , Antimicrobial Cationic Peptides/chemical synthesis , Antimicrobial Cationic Peptides/immunology , Antiviral Agents/chemical synthesis , Antiviral Agents/immunology , Clinical Trials as Topic , Coronavirus/drug effects , Coronavirus/physiology , Coronavirus Infections/immunology , Coronavirus Infections/virology , Humans , Immunomodulation , Respiratory Tract Infections/drug therapy , Respiratory Tract Infections/epidemiology , Respiratory Tract Infections/immunology , Respiratory Tract Infections/virology
9.
Int J Mol Sci ; 22(9)2021 Apr 28.
Article in English | MEDLINE | ID: covidwho-1359279

ABSTRACT

Deeply understanding the virus-host interaction is a prerequisite for developing effective anti-viral strategies. Traditionally, the transporter associated with antigen processing type 1 (TAP1) is critical for antigen presentation to regulate adaptive immunity. However, its role in controlling viral infections through modulating innate immune signaling is not yet fully understood. In the present study, we reported that TAP1, as a product of interferon-stimulated genes (ISGs), had broadly antiviral activity against various viruses such as herpes simplex virus 1 (HSV-1), adenoviruses (AdV), vesicular stomatitis virus (VSV), dengue virus (DENV), Zika virus (ZIKV), and influenza virus (PR8) etc. This antiviral activity by TAP1 was further confirmed by series of loss-of-function and gain-of-function experiments. Our further investigation revealed that TAP1 significantly promoted the interferon (IFN)-ß production through activating the TANK binding kinase-1 (TBK1) and the interferon regulatory factor 3 (IRF3) signaling transduction. Our work highlighted the broadly anti-viral function of TAP1 by modulating innate immunity, which is independent of its well-known function of antigen presentation. This study will provide insights into developing novel vaccination and immunotherapy strategies against emerging infectious diseases.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 2/immunology , Antiviral Agents/immunology , Host Microbial Interactions/immunology , Interferon Type I/biosynthesis , ATP Binding Cassette Transporter, Subfamily B, Member 2/antagonists & inhibitors , ATP Binding Cassette Transporter, Subfamily B, Member 2/deficiency , ATP Binding Cassette Transporter, Subfamily B, Member 2/genetics , Animals , Gene Knockout Techniques , HEK293 Cells , Humans , Immunity, Innate , Interferon Regulatory Factor-3/immunology , Mice , Models, Immunological , RAW 264.7 Cells , Toll-Like Receptors/agonists , Virus Diseases/immunology
10.
J Exp Med ; 218(10)2021 10 04.
Article in English | MEDLINE | ID: covidwho-1345702

ABSTRACT

IFN-I and IFN-III immunity in the nasal mucosa is poorly characterized during SARS-CoV-2 infection. We analyze the nasal IFN-I/III signature, namely the expression of ISGF-3-dependent IFN-stimulated genes, in mildly symptomatic COVID-19 patients and show its correlation with serum IFN-α2 levels, which peak at symptom onset and return to baseline from day 10 onward. Moreover, the nasal IFN-I/III signature correlates with the nasopharyngeal viral load and is associated with the presence of infectious viruses. By contrast, we observe low nasal IFN-I/III scores despite high nasal viral loads in a subset of critically ill COVID-19 patients, which correlates with the presence of autoantibodies (auto-Abs) against IFN-I in both blood and nasopharyngeal mucosa. In addition, functional assays in a reconstituted human airway epithelium model of SARS-CoV-2 infection confirm the role of such auto-Abs in abrogating the antiviral effects of IFN-I, but not those of IFN-III. Thus, IFN-I auto-Abs may compromise not only systemic but also local antiviral IFN-I immunity at the early stages of SARS-CoV-2 infection.


Subject(s)
Autoantibodies/immunology , COVID-19/immunology , Interferon Type I/immunology , SARS-CoV-2/immunology , Adult , Aged , Animals , Antiviral Agents/immunology , Antiviral Agents/pharmacology , Autoantibodies/blood , COVID-19/blood , COVID-19/virology , Chlorocebus aethiops , Female , Humans , Interferon Type I/pharmacology , Longitudinal Studies , Male , Middle Aged , Nasal Cavity/immunology , Nasal Cavity/virology , Prospective Studies , SARS-CoV-2/physiology , Vero Cells , Viral Load/drug effects , Viral Load/immunology , Virus Replication/drug effects , Virus Replication/immunology
11.
Viruses ; 13(7)2021 07 15.
Article in English | MEDLINE | ID: covidwho-1335222

ABSTRACT

Viral infections cause a variety of acute and chronic human diseases, sometimes resulting in small local outbreaks, or in some cases spreading across the globe and leading to global pandemics. Understanding and exploiting virus-host interactions is instrumental for identifying host factors involved in viral replication, developing effective antiviral agents, and mitigating the severity of virus-borne infectious diseases. The diversity of CRISPR systems and CRISPR-based tools enables the specific modulation of innate immune responses and has contributed impressively to the fields of virology and immunology in a very short time. In this review, we describe the most recent advances in the use of CRISPR systems for basic and translational studies of virus-host interactions.


Subject(s)
Antiviral Agents/immunology , Antiviral Agents/pharmacology , CRISPR-Cas Systems , Virus Diseases/immunology , Animals , Exoribonucleases/metabolism , Host Microbial Interactions/immunology , Humans , Immune Evasion , Immunity, Innate , Interferons/genetics , Interferons/immunology , RNA Editing , Transcriptome , Virus Diseases/virology , Virus Internalization , Virus Replication/drug effects
12.
Cytokine ; 146: 155637, 2021 10.
Article in English | MEDLINE | ID: covidwho-1333350

ABSTRACT

Interferons have prominent roles in various pathophysiological conditions, mostly related to inflammation. Interferon-gamma (IFNγ) was, initially discovered as a potent antiviral agent, over 50 years ago, and has recently garnered renewed interest as a promising factor involved in both innate and adaptive immunity. When new disease epidemics appear such as SARS-CoV (severe acute respiratory syndrome coronavirus), MERS-CoV (Middle East respiratory syndrome coronavirus), IAV (Influenza A virus), and in particular the current SARS-CoV-2 pandemic, it is especially timely to review the complexity of immune system responses to viral infections. Here we consider the controversial roles of effectors like IFNγ, discussing its actions in immunomodulation and immunotolerance. We explore the possibility that modulation of IFNγ could be used to influence the course of such infections. Importantly, not only could endogenous expression of IFNγ influence the outcome, there are existing IFNγ therapeutics that can readily be applied in the clinic. However, our understanding of the molecular mechanisms controlled by IFNγ suggests that the exact timing for application of IFNγ-based therapeutics could be crucial: it should be earlier to significantly reduce the viral load and thus decrease the overall severity of the disease.


Subject(s)
Adaptive Immunity/immunology , COVID-19/immunology , Immune Tolerance/immunology , Immunity, Innate/immunology , Interferon-gamma/immunology , Antiviral Agents/immunology , Antiviral Agents/therapeutic use , COVID-19/drug therapy , COVID-19/virology , Humans , Interferon-gamma/therapeutic use , Receptors, Interferon/immunology , SARS-CoV-2/drug effects , SARS-CoV-2/immunology , SARS-CoV-2/physiology , Signal Transduction/immunology
13.
Inflammopharmacology ; 29(5): 1331-1346, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1333093

ABSTRACT

The pandemic coronavirus disease 2019 (COVID-19) is instigated by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that is mainly transmitted via the inhalation route and characterized by fever, coughing and shortness of breath. COVID-19 affects all age groups with no single cure. The drug discovery, manufacturing, and safety studies require extensive time and sources and, therefore, struggled to match the exponential spread of COVID-19. Yet, various repurposed drugs (antivirals, immune-modulators, nucleotide analogues), and convalescent plasma therapy have been authorized for emergency use against COVID-19 by Food and Drug Administration under certain limits and conditions. The discovery of vaccine is the biggest milestone achieved during the current pandemic era. About nine vaccines were developed for human use with varying claims of efficacy. The rapid emergence of mutations in SARS-CoV-2, suspected adverse drug reactions of current therapies in special population groups and limited availability of drugs in developing countries necessitate the development of more efficacious, safe and cheap drugs/vaccines for treatment and prevention of COVID-19. Keeping in view these limitations, the current review provides an update on the efficacy and safety of the repurposed, and natural drugs to treat COVID-19 as well as the vaccines used for its prophylaxis.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19 Vaccines/therapeutic use , COVID-19/immunology , COVID-19/therapy , Drug Repositioning/trends , Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Angiotensin-Converting Enzyme 2/immunology , Animals , Antiviral Agents/immunology , Antiviral Agents/therapeutic use , Biological Products/immunology , Biological Products/therapeutic use , COVID-19/epidemiology , Drug Repositioning/methods , Humans , Immunization, Passive , Immunologic Factors/immunology , Immunologic Factors/therapeutic use
14.
Biomed Pharmacother ; 142: 111957, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1330662

ABSTRACT

The outbreak of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Wuhan, China, in December 2019, and its global dissemination became the coronavirus disease 2019 (COVID-19) pandemic declared by the World Health Organization (WHO) on 11 March 2020. In patients undergoing immunotherapy, the effect and path of viral infection remain uncertain. In addition, viral-infected mice and humans show T-cell exhaustion, which is identified after infection with SARS-CoV-2. Notably, they regain their T-cell competence and effectively prevent viral infection when treated with anti-PD-1 antibodies. Four clinical trials are officially open to evaluate anti-PD-1 antibody administration's effectiveness for cancer and non-cancer individuals influenced by COVID-19 based on these findings. The findings may demonstrate the hypothesis that a winning strategy to combat SARS-CoV-2 infection could be the restoration of exhausted T-cells. In this review, we outline the potential protective function of the anti-PD-1 blockade against SARS-CoV-2 infection with the aim to develop SARS-CoV-2 therapy.


Subject(s)
COVID-19 , SARS-CoV-2 , Animals , Antiviral Agents/immunology , COVID-19/drug therapy , COVID-19/immunology , Humans , Immune Checkpoint Inhibitors/immunology , Immune Checkpoint Inhibitors/pharmacology , Immunotherapy/methods , Mice , Protective Agents/pharmacology , SARS-CoV-2/drug effects , SARS-CoV-2/physiology , T-Lymphocytes/immunology
15.
mSphere ; 6(4): e0057121, 2021 08 25.
Article in English | MEDLINE | ID: covidwho-1329040

ABSTRACT

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is ongoing and has shown the community that flexible methods for rapidly identifying and screening candidate antivirals are needed. Assessing virus-neutralizing activity of human serum to monitor population immunity and response to infection and vaccination is key to pandemic control. We developed a virus neutralization platform strategy that relies only on bioinformatic and genetic information of the virus of interest. The platform uses viral envelope glycoprotein cDNAs to set up an assay that mimics multicycle infection but is safe and, therefore, amenable to biosafety level 2 (BSL2) conditions for viruses that require BSL3 facilities (e.g., SARS-CoV-1 and SARS-CoV-2). As a complement to this platform, we present a new cell-based immunofluorescent (CBI) assay that uses SARS-CoV-2 spike protein (S)-expressing cells to accurately measure the neutralization potential of human sera and is readily adaptable to variants of concern. These methods should be useful additions to the tools for assessing antiviral immunity, whether acquired via natural infection or vaccines. IMPORTANCE Assays for rapid biosafety level 2 (BSL2) evaluation of neutralizing properties of antibodies acquired via natural infection or through vaccination is urgently needed. Here, we propose a combinatorial approach in which sera are screened for SARS-CoV-2 spike protein (S) binding using a cell-based immunofluorescent (CBI) assay, and positive samples are further evaluated in a pseudotyped viral multicycle infection-mimicking protocol under BSL2 conditions.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Antiviral Agents/immunology , COVID-19/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Animals , COVID-19/virology , Cell Line , Chlorocebus aethiops , HEK293 Cells , Humans , Neutralization Tests/methods , Pandemics/prevention & control , Vero Cells
16.
PLoS One ; 16(7): e0254374, 2021.
Article in English | MEDLINE | ID: covidwho-1320545

ABSTRACT

While establishing worldwide collective immunity with anti SARS-CoV-2 vaccines, COVID-19 remains a major health issue with dramatic ensuing economic consequences. In the transition, repurposing existing drugs remains the fastest cost-effective approach to alleviate the burden on health services, most particularly by reducing the incidence of the acute respiratory distress syndrome associated with severe COVID-19. We undertook a computational repurposing approach to identify candidate therapeutic drugs to control progression towards severe airways inflammation during COVID-19. Molecular profiling data were obtained from public sources regarding SARS-CoV-2 infected epithelial or endothelial cells, immune dysregulations associated with severe COVID-19 and lung inflammation induced by other respiratory viruses. From these data, we generated a protein-protein interactome modeling the evolution of lung inflammation during COVID-19 from inception to an established cytokine release syndrome. This predictive model assembling severe COVID-19-related proteins supports a role for known contributors to the cytokine storm such as IL1ß, IL6, TNFα, JAK2, but also less prominent actors such as IL17, IL23 and C5a. Importantly our analysis points out to alarmins such as TSLP, IL33, members of the S100 family and their receptors (ST2, RAGE) as targets of major therapeutic interest. By evaluating the network-based distances between severe COVID-19-related proteins and known drug targets, network computing identified drugs which could be repurposed to prevent or slow down progression towards severe airways inflammation. This analysis confirmed the interest of dexamethasone, JAK2 inhibitors, estrogens and further identified various drugs either available or in development interacting with the aforementioned targets. We most particularly recommend considering various inhibitors of alarmins or their receptors, currently receiving little attention in this indication, as candidate treatments for severe COVID-19.


Subject(s)
Alarmins/immunology , Antiviral Agents/pharmacology , COVID-19/complications , Drug Repositioning , Pneumonia/complications , Pneumonia/drug therapy , Antiviral Agents/immunology , Antiviral Agents/therapeutic use , Humans , Pneumonia/immunology
17.
Cell Res ; 31(9): 1011-1023, 2021 09.
Article in English | MEDLINE | ID: covidwho-1315592

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global crisis, urgently necessitating the development of safe, efficacious, convenient-to-store, and low-cost vaccine options. A major challenge is that the receptor-binding domain (RBD)-only vaccine fails to trigger long-lasting protective immunity if used alone for vaccination. To enhance antigen processing and cross-presentation in draining lymph nodes (DLNs), we developed an interferon (IFN)-armed RBD dimerized by an immunoglobulin fragment (I-R-F). I-R-F efficiently directs immunity against RBD to DLNs. A low dose of I-R-F induces not only high titers of long-lasting neutralizing antibodies (NAbs) but also more comprehensive T cell responses than RBD. Notably, I-R-F provides comprehensive protection in the form of a one-dose vaccine without an adjuvant. Our study shows that the pan-epitope modified human I-R-F (I-P-R-F) vaccine provides rapid and complete protection throughout the upper and lower respiratory tracts against a high-dose SARS-CoV-2 challenge in rhesus macaques. Based on these promising results, we have initiated a randomized, placebo-controlled, phase I/II trial of the human I-P-R-F vaccine (V-01) in 180 healthy adults, and the vaccine appears safe and elicits strong antiviral immune responses. Due to its potency and safety, this engineered vaccine may become a next-generation vaccine candidate in the global effort to overcome COVID-19.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/immunology , Immunogenicity, Vaccine/immunology , Protein Binding/immunology , Protein Domains/immunology , SARS-CoV-2/immunology , Adolescent , Adult , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Antiviral Agents/immunology , Cell Line , Chlorocebus aethiops , Double-Blind Method , Female , HEK293 Cells , Humans , Interferons/immunology , Macaca mulatta , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Middle Aged , Vaccination/methods , Vero Cells , Young Adult
18.
Cells ; 10(7)2021 07 11.
Article in English | MEDLINE | ID: covidwho-1308300

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing coronavirus disease 2019 (COVID-19) emerged in late 2019 and resulted in a devastating pandemic. Although the first approved vaccines were already administered by the end of 2020, worldwide vaccine availability is still limited. Moreover, immune escape variants of the virus are emerging against which the current vaccines may confer only limited protection. Further, existing antivirals and treatment options against COVID-19 show only limited efficacy. Influenza A virus (IAV) defective interfering particles (DIPs) were previously proposed not only for antiviral treatment of the influenza disease but also for pan-specific treatment of interferon (IFN)-sensitive respiratory virus infections. To investigate the applicability of IAV DIPs as an antiviral for the treatment of COVID-19, we conducted in vitro co-infection experiments with cell culture-derived DIPs and the IFN-sensitive SARS-CoV-2 in human lung cells. We show that treatment with IAV DIPs leads to complete abrogation of SARS-CoV-2 replication. Moreover, this inhibitory effect was dependent on janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling. Further, our results suggest boosting of IFN-induced antiviral activity by IAV DIPs as a major contributor in suppressing SARS-CoV-2 replication. Thus, we propose IAV DIPs as an effective antiviral agent for treatment of COVID-19, and potentially also for suppressing the replication of new variants of SARS-CoV-2.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Immunity, Innate/drug effects , SARS-CoV-2/drug effects , Animals , Antiviral Agents/immunology , COVID-19/immunology , Cell Line, Tumor , Chlorocebus aethiops , Defective Viruses/immunology , Humans , Influenza A virus/immunology , SARS-CoV-2/immunology , SARS-CoV-2/physiology , Vero Cells , Virus Replication/drug effects
19.
Int Immunopharmacol ; 96: 107797, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1300822

ABSTRACT

Specific antibodies against SARS-CoV-2 structural protein have a wide range of effects in the diagnose, prevention and treatment of the COVID-19 epidemic. Among them, egg yolk immunoglobulin Y (IgY), which has high safety, high yield, and without inducing antibody-dependent enhancement, is an important biological candidate. In this study, specific IgY against the conservative nucleocapsid protein (NP) of SARS-CoV-2 was obtained by immunizing hens. Through a series of optimized precipitation and ultrafiltration extraction schemes, its purity was increased to 98%. The hyperimmune IgY against NP (N-IgY) at a titer of 1:50,000 showed strong NP binding ability, which laid the foundation of N-IgY's application targeting NP. In an in vitro immunoregulatory study, N-IgY (1 mg/mL) modulated NP-induced immune response by alleviating type II interferon secretion stimulated by NP (20 µg/mL). In summary, N-IgY can be mass produced by achievable method, which endows it with potential value against the current COVID-19 pandemic.


Subject(s)
Antibodies/immunology , Antiviral Agents/immunology , COVID-19/immunology , Immunoglobulins/immunology , Immunologic Factors/immunology , Interferon-gamma/metabolism , SARS-CoV-2/immunology , Animals , Antibodies/pharmacology , Antiviral Agents/pharmacology , COVID-19/therapy , Chickens , Drug Development , Egg Yolk/chemistry , Egg Yolk/metabolism , Humans , Immunity , Immunoglobulins/pharmacology , Immunologic Factors/pharmacology , Immunomodulation , In Vitro Techniques , Nucleocapsid Proteins/immunology , Nucleocapsid Proteins/metabolism , SARS-CoV-2/metabolism
20.
Molecules ; 26(13)2021 Jun 24.
Article in English | MEDLINE | ID: covidwho-1288959

ABSTRACT

The COVID-19 pandemic, as well as the more general global increase in viral diseases, has led researchers to look to the plant kingdom as a potential source for antiviral compounds. Since ancient times, herbal medicines have been extensively applied in the treatment and prevention of various infectious diseases in different traditional systems. The purpose of this review is to highlight the potential antiviral activity of plant compounds as effective and reliable agents against viral infections, especially by viruses from the coronavirus group. Various antiviral mechanisms shown by crude plant extracts and plant-derived bioactive compounds are discussed. The understanding of the action mechanisms of complex plant extract and isolated plant-derived compounds will help pave the way towards the combat of this life-threatening disease. Further, molecular docking studies, in silico analyses of extracted compounds, and future prospects are included. The in vitro production of antiviral chemical compounds from plants using molecular pharming is also considered. Notably, hairy root cultures represent a promising and sustainable way to obtain a range of biologically active compounds that may be applied in the development of novel antiviral agents.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Plant Extracts/pharmacology , Plants, Medicinal/chemistry , SARS-CoV-2/drug effects , Antiviral Agents/chemistry , Antiviral Agents/immunology , Antiviral Agents/therapeutic use , Computer Simulation , Humans , Molecular Farming/methods , Plant Extracts/chemistry , Plant Extracts/immunology , Plant Extracts/therapeutic use , Plants, Medicinal/immunology , SARS-CoV-2/physiology , Virus Replication/drug effects
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