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1.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-335226

ABSTRACT

To address the need for multivalent vaccines against Coronaviridae that can be rapidly developed and manufactured, we compared antibody responses against SARS-CoV, SARS-CoV-2, and several variants of concern in mice immunized with mRNA-lipid nanoparticle vaccines encoding homodimers or heterodimers of SARS-CoV/SARS-CoV-2 receptor-binding domains. All vaccine constructs induced robust anti-viral antibody responses, and the heterodimeric vaccine elicited an IgG response capable of cross-neutralizing SARS-CoV, SARS-CoV-2 Wuhan-Hu-1, B.1.351 (beta), and B.1.617.2 (delta) variants.

2.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-325195

ABSTRACT

Background: COVID-19 is a globally emerging infectious disease. As the global epidemic continues to spread, the risk of COVID-19 transmission and diffusion in the world will also remain. Currently, several studies describing its clinical characteristics have focused on the initial outbreak, but rarely to the later stage. Here we described clinical characteristics, risk factors for disease severity and in-hospital outcome in patients with COVID-19 pneumonia from Wuhan. Methods: : Patients with COVID-19 pneumonia admitted to Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology from February 13 to March 8, 2020, were retrospectively enrolled. Multivariable logistic regression analysis was used to identify risk factors for disease severity and in-hospital outcome and establish predictive models. Receiver operating characteristic (ROC) curve was used to assess the predictive value of above models. Results: : 106 (61.3%) of the patients were female. The mean age of study populations was 62.0 years, of whom 73 (42.2%) had underlying comorbidities mainly including hypertension (24.9%). The most common symptoms on admission were fever (67.6%) and cough (60.1%), digestive symptoms (22.0%) was also very common. Older age (OR: 3.420;95%Cl: 1.415-8.266;P=0.006), diarrhea (OR: 0.143;95%Cl: 0.033-0.611;P=0.009) and lymphopenia (OR: 4.769;95%Cl: 2.019-11.266;P=0.000) were associated with severe illness on admission;the area under the ROC curve (AUC) of predictive model were 0.860 (95%CI: 0.802-0.918;P=0.000). Older age (OR: 0.309;95%Cl: 0.142-0.674;P=0.003), leucopenia (OR: 0.165;95%Cl: 0.034-0.793;P=0.025), increased lactic dehydrogenase (OR: 0.257;95%Cl: 0.100-0.659;P=0.005) and interleukins-6 levels (OR: 0.294;95%Cl: 0.099-0.872;P=0.027) were associated with poor in-hospital outcome;AUC of predictive model were 0.752 (95%CI: 0.681-0.824;P=0.000). Conclusion: Older patients with diarrhea and lymphopenia need early identification and timely intervention to prevent the progression to severe COVID-19 pneumonia. However, older patients with leucopenia, increased lactic dehydrogenase and interleukins-6 levels are at a high risk for poor in-hospital outcome. Trial registration: ChiCTR2000029549

3.
J Med Chem ; 65(4): 2866-2879, 2022 02 24.
Article in English | MEDLINE | ID: covidwho-1440451

ABSTRACT

The emergence of a new coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), presents an urgent public health crisis. Without available targeted therapies, treatment options remain limited for COVID-19 patients. Using medicinal chemistry and rational drug design strategies, we identify a 2-phenyl-1,2-benzoselenazol-3-one class of compounds targeting the SARS-CoV-2 main protease (Mpro). FRET-based screening against recombinant SARS-CoV-2 Mpro identified six compounds that inhibit proteolysis with nanomolar IC50 values. Preincubation dilution experiments and molecular docking determined that the inhibition of SARS-CoV-2 Mpro can occur by either covalent or noncovalent mechanisms, and lead E04 was determined to inhibit Mpro competitively. Lead E24 inhibited viral replication with a nanomolar EC50 value (844 nM) in SARS-CoV-2-infected Vero E6 cells and was further confirmed to impair SARS-CoV-2 replication in human lung epithelial cells and human-induced pluripotent stem cell-derived 3D lung organoids. Altogether, these studies provide a structural framework and mechanism of Mpro inhibition that should facilitate the design of future COVID-19 treatments.


Subject(s)
Antiviral Agents/pharmacology , Benzothiazoles/pharmacology , Coronavirus 3C Proteases/antagonists & inhibitors , Cysteine Proteinase Inhibitors/pharmacology , Drug Discovery , SARS-CoV-2/drug effects , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Benzothiazoles/chemistry , COVID-19/drug therapy , COVID-19/metabolism , Chlorocebus aethiops , Coronavirus 3C Proteases/isolation & purification , Coronavirus 3C Proteases/metabolism , Crystallography, X-Ray , Cysteine Proteinase Inhibitors/chemical synthesis , Cysteine Proteinase Inhibitors/chemistry , Dose-Response Relationship, Drug , Fluorescence Resonance Energy Transfer , Humans , Microbial Sensitivity Tests , Molecular Docking Simulation , Molecular Structure , SARS-CoV-2/enzymology , Vero Cells , Virus Replication/drug effects
4.
Interdiscip Sci ; 14(1): 55-63, 2022 Mar.
Article in English | MEDLINE | ID: covidwho-1401097

ABSTRACT

The novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide for almost 2 years. It starts from viral adherence to host cells through an interaction between spike glycoprotein 1 (S1) containing a receptor-binding domain (RBD) and human angiotensin-converting enzyme-2 (ACE2). One of the useful strategies to prevent SARS-CoV-2 infection is to inhibit the attachment of RBD to ACE2. Therefore, the current work proposed potent peptides against SARS-CoV-2 infection by carrying out MM-PBSA calculation based on the binding of 52 antiviral peptides (AVPs) to RBD. Considering the binding free energies of AVPs to RBD, cyanovirin-N (CV-N) showed the strongest RBD binding affinity among 52 AVPs. Upon structural analysis of RBD complex with CV-N, it was observed that 12 of the 13 key residues of RBD binding to ACE2 were hijacked by CV-N. CV-N bound to RBD at a smaller affinity of 14.9 nM than that of ACE2 and inhibited the recruitment of S1 to human alveolar epithelial cells. Further analysis revealed that CV-N suppressed SARS-CoV-2 S pseudovirion infection with a half-maximal inhibitory concentration (IC50) of 18.52 µg/mL. This study demonstrated a drug screening for AVPs against SARS-CoV-2 and discovered a peptide with inspiring antiviral properties, which provided a promising strategy for the COVID-19 therapeutic approach.


Subject(s)
Biological Products , COVID-19 , Biological Products/pharmacology , COVID-19/drug therapy , Drug Evaluation, Preclinical , Humans , Protein Binding , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism
5.
ACS Infect Dis ; 7(6): 1545-1554, 2021 06 11.
Article in English | MEDLINE | ID: covidwho-1182792

ABSTRACT

SARS-CoV-2 infection begins with the association of its spike 1 (S1) protein with host angiotensin-converting enzyme-2 (ACE2). Targeting the interaction between S1 and ACE2 is a practical strategy against SARS-CoV-2 infection. Herein, we show encouraging results indicating that human cathelicidin LL37 can simultaneously block viral S1 and cloak ACE2. LL37 binds to the receptor-binding domain (RBD) of S1 with high affinity (11.2 nM) and decreases subsequent recruitment of ACE2. Owing to the RBD blockade, LL37 inhibits SARS-CoV-2 S pseudovirion infection, with a half-maximal inhibitory concentration of 4.74 µg/mL. Interestingly, LL37 also binds to ACE2 with an affinity of 25.5 nM and cloaks the ligand-binding domain (LBD), thereby decreasing S1 adherence and protecting cells against pseudovirion infection in vitro. Intranasal administration of LL37 to C57 mice infected with adenovirus expressing human ACE2 either before or after pseudovirion invasion decreased lung infection. The study identified a versatile antimicrobial peptide in humans as an inhibitor of SARS-CoV-2 attachment using dual mechanisms, thus providing a potential candidate for coronavirus disease 2019 (COVID-19) prevention and treatment.


Subject(s)
Antimicrobial Cationic Peptides/pharmacology , COVID-19 , Spike Glycoprotein, Coronavirus , Virus Attachment/drug effects , Angiotensin-Converting Enzyme 2 , Animals , COVID-19/prevention & control , Humans , Mice , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/genetics
6.
ACS Nano ; 15(4): 6340-6351, 2021 04 27.
Article in English | MEDLINE | ID: covidwho-1139707

ABSTRACT

The ongoing COVID-19 pandemic worldwide necessitates the development of therapeutics against SARS-CoV-2. ACE2 is the main receptor of SARS-CoV-2 S1 and mediates viral entry into host cells. Herein, membrane nanoparticles (NPs) prepared from ACE2-rich cells were discovered to have potent capacity to block SARS-CoV-2 infection. The membranes of human embryonic kidney-239T cells highly expressing ACE2 were applied to prepare NPs using an extrusion method. The nanomaterials, termed ACE2-NPs, contained 265.1 ng mg-1 ACE2 on the surface and acted as baits to trap S1 in a dose-dependent manner, resulting in reduced recruitment of the viral ligand to HK-2 human renal tubular epithelial cells. Aside from affecting receptor recongnition, S1 translocated to the cytoplasm and induced apoptosis by reducing optic atrophy 1 expression and increasing cytochrome c release, which was also inhibited by ACE2-NPs. Further investigations revealed that ACE2-NPs efficiently suppressed SARS-CoV-2 S pseudovirions entry into host cells and blocked viral infection in vitro and in vivo. This study characterizes easy-to-produce memrbane nanoantagonists of SARS-CoV-2 that enrich the existing antiviral arsenal and provide possibilities for COVID-19 treatment.


Subject(s)
COVID-19 , Nanoparticles , COVID-19/drug therapy , Humans , Pandemics , Peptidyl-Dipeptidase A , SARS-CoV-2 , Spike Glycoprotein, Coronavirus
7.
Stem Cell Reports ; 16(3): 437-445, 2021 03 09.
Article in English | MEDLINE | ID: covidwho-1084274

ABSTRACT

COVID-19 is a transmissible respiratory disease caused by a novel coronavirus, SARS-CoV-2, and has become a global health emergency. There is an urgent need for robust and practical in vitro model systems to investigate viral pathogenesis. Here, we generated human induced pluripotent stem cell (iPSC)-derived lung organoids (LORGs), cerebral organoids (CORGs), neural progenitor cells (NPCs), neurons, and astrocytes. LORGs containing epithelial cells, alveolar types 1 and 2, highly express ACE2 and TMPRSS2 and are permissive to SARS-CoV-2 infection. SARS-CoV-2 infection induces interferons, cytokines, and chemokines and activates critical inflammasome pathway genes. Spike protein inhibitor, EK1 peptide, and TMPRSS2 inhibitors (camostat/nafamostat) block viral entry in LORGs. Conversely, CORGs, NPCs, astrocytes, and neurons express low levels of ACE2 and TMPRSS2 and correspondingly are not highly permissive to SARS-CoV-2 infection. Infection in neuronal cells activates TLR3/7, OAS2, complement system, and apoptotic genes. These findings will aid in understanding COVID-19 pathogenesis and facilitate drug discovery.


Subject(s)
Brain/virology , COVID-19/virology , Induced Pluripotent Stem Cells/virology , Lung/virology , Neural Stem Cells/virology , Organoids/virology , SARS-CoV-2/pathogenicity , Apoptosis/physiology , Brain/metabolism , COVID-19/metabolism , Cells, Cultured , Complement System Proteins/metabolism , Epithelial Cells/metabolism , Epithelial Cells/virology , Humans , Induced Pluripotent Stem Cells/metabolism , Inflammation/metabolism , Inflammation/virology , Lung/metabolism , Neural Stem Cells/metabolism , Neurons/metabolism , Neurons/virology , Organoids/metabolism , Serine Endopeptidases/metabolism , Signal Transduction/physiology , Stem Cells/metabolism , Stem Cells/virology
8.
EMBO J ; 39(21): e106057, 2020 11 02.
Article in English | MEDLINE | ID: covidwho-846583

ABSTRACT

Coronavirus disease 2019 (COVID-19) is caused by SARS-CoV-2 and has spread across the globe. SARS-CoV-2 is a highly infectious virus with no vaccine or antiviral therapy available to control the pandemic; therefore, it is crucial to understand the mechanisms of viral pathogenesis and the host immune responses to SARS-CoV-2. SARS-CoV-2 is a new member of the betacoronavirus genus like other closely related viruses including SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV). Both SARS-CoV and MERS-CoV have caused serious outbreaks and epidemics in the past eighteen years. Here, we report that one of the interferon-stimulated genes (ISGs), cholesterol 25-hydroxylase (CH25H), is induced by SARS-CoV-2 infection in vitro and in COVID-19-infected patients. CH25H converts cholesterol to 25-hydrocholesterol (25HC) and 25HC shows broad anti-coronavirus activity by blocking membrane fusion. Furthermore, 25HC inhibits USA-WA1/2020 SARS-CoV-2 infection in lung epithelial cells and viral entry in human lung organoids. Mechanistically, 25HC inhibits viral membrane fusion by activating the ER-localized acyl-CoA:cholesterol acyltransferase (ACAT) which leads to the depletion of accessible cholesterol from the plasma membrane. Altogether, our results shed light on a potentially broad antiviral mechanism by 25HC through depleting accessible cholesterol on the plasma membrane to suppress virus-cell fusion. Since 25HC is a natural product with no known toxicity at effective concentrations, it provides a potential therapeutic candidate for COVID-19 and emerging viral diseases in the future.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Cholesterol/metabolism , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Respiratory Mucosa/virology , Steroid Hydroxylases/pharmacology , Virus Internalization/drug effects , Acetyl-CoA C-Acetyltransferase/metabolism , Animals , COVID-19 , Cell Line , Cell Membrane/drug effects , Cell Membrane/metabolism , Chlorocebus aethiops , Enzyme Activation/drug effects , Humans , Middle East Respiratory Syndrome Coronavirus/drug effects , Organoids/virology , Pandemics , Respiratory Mucosa/drug effects , SARS Virus/drug effects , SARS-CoV-2 , Vero Cells
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