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1.
PLoS Negl Trop Dis ; 16(4): e0010363, 2022 04.
Article in English | MEDLINE | ID: covidwho-1808522

ABSTRACT

COVID-19 caused by SARS-CoV-2 has posed a significant threat to global public health since its outbreak in late 2019. Although there are a few drugs approved for clinical treatment to combat SARS-CoV-2 infection currently, the severity of the ongoing global pandemic still urges the efforts to discover new antiviral compounds. As the viral spike (S) protein plays a key role in mediating virus entry, it becomes a potential target for the design of antiviral drugs against COVID-19. Here, we tested the antiviral activity of berbamine hydrochloride, a bis-benzylisoquinoline alkaloid, against SARS-CoV-2 infection. We found that berbamine hydrochloride could efficiently inhibit SARS-CoV-2 infection in different cell lines. Further experiments showed berbamine hydrochloride inhibits SARS-CoV-2 infection by targeting the viral entry into host cells. Moreover, berbamine hydrochloride and other bis-benzylisoquinoline alkaloids could potently inhibit S-mediated cell-cell fusion. Furthermore, molecular docking results implied that the berbamine hydrochloride could bind to the post fusion core of SARS-CoV-2 S2 subunit. Therefore, berbamine hydrochloride may represent a potential efficient antiviral agent against SARS-CoV-2 infection.


Subject(s)
Benzylisoquinolines , COVID-19 , Antiviral Agents/pharmacology , Benzylisoquinolines/pharmacology , COVID-19/drug therapy , Humans , Membrane Fusion , Molecular Docking Simulation , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Virus Internalization
3.
Signal Transduct Target Ther ; 6(1): 369, 2021 10 25.
Article in English | MEDLINE | ID: covidwho-1483125

ABSTRACT

The lung is the prophylaxis target against SARS-CoV-2 infection, and neutralizing antibodies are a leading class of biological products against various infectious viral pathogen. In this study, we develop a safe and cost-effective platform to express neutralizing antibody in the lung with replicating mRNA basing on alphavirus replicon particle (VRP) delivery system, to prevent SARS-CoV-2 infections. First, a modified VEEV replicon with two subgenomic (sg) promoters was engineered to translate the light and heavy chains of antibody simultaneously, for expression and assembly of neutralizing anti-SARS-CoV-2 antibody CB6. Second, the feasibility and protective efficacy of replicating mRNA against SARS-CoV-2 infection were demonstrated through both in vitro and in vivo assays. The lung target delivery with the help of VRP system resulted in efficiently block SARS-CoV-2 infection with reducing viral titer and less tissue damage in the lung of mice. Overall, our data suggests that expressing neutralizing antibodies in the lungs with the help of self-replicating mRNA could potentially be a promising prophylaxis approach against SARS-CoV-2 infection.


Subject(s)
Alphavirus , Antibodies, Neutralizing , Antibodies, Viral , COVID-19/therapy , Replicon , SARS-CoV-2/metabolism , Animals , Antibodies, Neutralizing/biosynthesis , Antibodies, Neutralizing/genetics , Antibodies, Viral/biosynthesis , Antibodies, Viral/genetics , COVID-19/genetics , COVID-19/metabolism , Chlorocebus aethiops , Cricetinae , Female , Mice , Mice, Inbred BALB C , RNA, Messenger/genetics , RNA, Messenger/metabolism , SARS-CoV-2/genetics , Vero Cells
4.
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
5.
Signal Transduct Target Ther ; 5(1): 218, 2020 10 03.
Article in English | MEDLINE | ID: covidwho-1387198

Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Cardiac Glycosides/pharmacology , Gene Expression Regulation/drug effects , Host-Pathogen Interactions/drug effects , Animals , Antiviral Agents/chemistry , Betacoronavirus/pathogenicity , Biological Products/chemistry , Biological Products/pharmacology , Bufanolides/chemistry , Bufanolides/pharmacology , COVID-19 , Cardiac Glycosides/chemistry , Cell Survival/drug effects , Chlorocebus aethiops , Chloroquine/chemistry , Chloroquine/pharmacology , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Digoxin/chemistry , Digoxin/pharmacology , High-Throughput Screening Assays , Host-Pathogen Interactions/genetics , Humans , Janus Kinases/antagonists & inhibitors , Janus Kinases/genetics , Janus Kinases/metabolism , Mitogen-Activated Protein Kinases/antagonists & inhibitors , Mitogen-Activated Protein Kinases/genetics , Mitogen-Activated Protein Kinases/metabolism , NF-E2-Related Factor 2/antagonists & inhibitors , NF-E2-Related Factor 2/genetics , NF-E2-Related Factor 2/metabolism , NF-kappa B/antagonists & inhibitors , NF-kappa B/genetics , NF-kappa B/metabolism , Pandemics , Phenanthrenes/chemistry , Phenanthrenes/pharmacology , Pneumonia, Viral/drug therapy , Pneumonia, Viral/virology , SARS-CoV-2 , Signal Transduction , Sodium-Potassium-Exchanging ATPase/antagonists & inhibitors , Sodium-Potassium-Exchanging ATPase/genetics , Sodium-Potassium-Exchanging ATPase/metabolism , Vero Cells , Virus Replication/drug effects
7.
J Gen Virol ; 102(5)2021 05.
Article in English | MEDLINE | ID: covidwho-1218063

ABSTRACT

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virus, which is highly pathogenic and classified as a biosafety level 3 (BSL-3) agent, has greatly threatened global health and efficacious antivirals are urgently needed. The high requirement of facilities to manipulate the live virus has limited the development of antiviral study. Here, we constructed a reporter replicon of SARS-CoV-2, which can be handled in a BSL-2 laboratory. The Renilla luciferase activity effectively reflected the transcription and replication levels of the replicon genome. We identified the suitability of the replicon in antiviral screening using the known inhibitors, and thus established the replicon-based high-throughput screening (HTS) assay for SARS-CoV-2. The application of the HTS assay was further validated using a few hit natural compounds, which were screened out in a SARS-CoV-2 induced cytopathic-effect-based HTS assay in our previous study. This replicon-based HTS assay will be a safe platform for SARS-CoV-2 antiviral screening in a BSL-2 laboratory without the live virus.


Subject(s)
Antiviral Agents/pharmacology , Drug Evaluation, Preclinical/methods , Replicon/drug effects , SARS-CoV-2/drug effects , Animals , COVID-19/drug therapy , Chlorocebus aethiops , Drug Discovery , High-Throughput Screening Assays/methods , Humans , Replicon/genetics , SARS-CoV-2/genetics , Vero Cells , Virus Replication/drug effects
8.
Virol Sin ; 36(5): 879-889, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1174014

ABSTRACT

The ongoing coronavirus disease 2019 (COVID-19) pandemic caused more than 96 million infections and over 2 million deaths worldwide so far. However, there is no approved vaccine available for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the disease causative agent. Vaccine is the most effective approach to eradicate a pathogen. The tests of safety and efficacy in animals are pivotal for developing a vaccine and before the vaccine is applied to human populations. Here we evaluated the safety, immunogenicity, and efficacy of an inactivated vaccine based on the whole viral particles in human ACE2 transgenic mouse and in non-human primates. Our data showed that the inactivated vaccine successfully induced SARS-CoV-2-specific neutralizing antibodies in mice and non-human primates, and subsequently provided partial (in low dose) or full (in high dose) protection of challenge in the tested animals. In addition, passive serum transferred from vaccine-immunized mice could also provide full protection from SARS-CoV-2 infection in mice. These results warranted positive outcomes in future clinical trials in humans.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19 , Animals , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , COVID-19/prevention & control , Mice , Mice, Transgenic , Primates , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Vaccines, Inactivated/immunology
9.
SciFinder; 2020.
Preprint | SciFinder | ID: ppcovidwho-4225

ABSTRACT

A review. Patients with low immune function are prone to novel coronavirus infection, which is consistent with the traditional Chinese medicine (TCM) concept of deficiency of vital Qi and invasion of toxin. At present, it is necessary to focus on the development of antiviral drugs, but it is also urgent to study the preparation for regulating the immune system. Mucosal tissue is an important barrier of human immune system. It has an independent immune system with unique functions and structures. It is the body′s first line of defense against infection, and is in direct contact with external antigens (such as food, symbiotic bacteria, viruses, etc.). In the resistance to viruses and infections, the mucosal immune system (such as respiratory mucosa, intestinal mucosa, etc.) plays an extremely important role, which can eliminate foreign pathogenic microorganisms or other foreign antigens, so that the virus does not invade the body tissue and cause damage to the body. There are more and more reports on the therapeutic effects of TCM through the mucosal immune system. This paper aims to explore the relationship between mucosal immunity and novel coronavirus pneumonia (COVID-19) and the intervention mechanism of TCM, so as to provide useful research methods and therapeutic ideas for the prevention and treatment of COVID-19.

11.
Emerg Microbes Infect ; 9(1): 1170-1173, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-324574

ABSTRACT

The emerging SARS-CoV-2 infection associated with the outbreak of viral pneumonia in China is ongoing worldwide. There are no approved antiviral therapies to treat this viral disease. Here we examined the antiviral abilities of three broad-spectrum antiviral compounds gemcitabine, lycorine and oxysophoridine against SARS-CoV-2 in cell culture. We found that all three tested compounds inhibited viral replication in Vero-E6 cells at noncytotoxic concentrations. The antiviral effect of gemcitabine was suppressed efficiently by the cytidine nucleosides. Additionally, combination of gemcitabine with oxysophoridine had an additive antiviral effect against SARS-CoV-2. Our results demonstrate that broad-spectrum antiviral compounds may have a priority for the screening of antiviral compounds against newly emerging viruses to control viral infection.


Subject(s)
Alkaloids/pharmacology , Amaryllidaceae Alkaloids/pharmacology , Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Deoxycytidine/analogs & derivatives , Phenanthridines/pharmacology , Virus Replication/drug effects , Animals , Betacoronavirus/growth & development , Betacoronavirus/metabolism , Cell Survival/drug effects , Chlorocebus aethiops , Chloroquine/pharmacology , Deoxycytidine/pharmacology , Dose-Response Relationship, Drug , Drug Combinations , Drug Synergism , SARS-CoV-2 , Vero Cells
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